diff --git a/R/load_nonmem.R b/R/load_nonmem.R index f8bedbf..21955f5 100644 --- a/R/load_nonmem.R +++ b/R/load_nonmem.R @@ -1,171 +1,171 @@ -## Loading Nonmem Files #### - -## FUNCTION LOAD CTL #### - -#' Load NONMEM ctl file into R -#' -#' Loads the NONMEM ctl file into R for translation to mrgsolve format. -#' -#' @param filename String of the NONMEM model name without the .ctl extension -#' @param dir String of the directory path to the NONMEM run files -#' -#' @return R dataframe of the NONMEM ctl file -#' -#' @examples -#' load_ctl(filename = "nonmem-model", dir = "path/to/directory/") -#' -#' @export -load_ctl <- function(filename = NULL, dir = ""){ - - ctl <- read.delim2(paste0(dir,filename,".ctl"), header = F) %>% - dplyr::mutate(V1 = trimws(V1, which = "both"))%>% # remove leading and trailing white space - dplyr::filter(substr(V1,1,1) != ";", V1 != "")%>% # remove white space or comment rows - dplyr::mutate(V1 = gsub(";.*","",V1))%>% # remove anything after comment - dplyr::mutate(FLG_BLOCK = ifelse(startsWith(V1, "$"), 1, 0))%>% # flag beginning of each block - dplyr::mutate(BLOCK = suppressWarnings(ifelse(FLG_BLOCK == 1, trimws(substr(V1,2,6), which = "both"), NA)))%>% # get block name - dplyr::mutate(BLOCK = zoo::na.locf(BLOCK, na.rm = F, fromLast = F)) # pull block name down until next block starts - - return(ctl) -} - -## FUNCTION LOAD EXT #### - -#' Load NONMEM ext file into R -#' -#' Loads the NONMEM ext file into R for capture of the final estimates. -#' -#' @param filename String of the NONMEM model name without the .ext extension -#' @param dir String of the directory path to the NONMEM run files -#' @param sigdig Numeric of the number of significant digits to round non-fixed thetas and etas to; -1 for no rounding -#' @param use.cnv Logical for whether to use the NONMEM cnv file for final parameter estimates instead of the ext file (\code{T} or \code{F}) -#' -#' @return R list of the NONMEM final OFV, parameter estimates, and IIV magnitudes -#' -#' @examples -#' load_ext(filename = "nonmem-model", dir = "path/to/directory/") -#' -#' @export -load_ext <- function(filename = NULL, dir = "", sigdig = -1, use.cnv = F){ - - ext00 <- read.table(paste0(dir,filename,".ext"),sep='',header=T,fill=T,na.strings=".", skip=1) - - if(class(ext00$ITERATION) != "numeric"){ - for(i in 1:ncol(ext00)){ - ext00[,i] <- as.numeric(ext00[,i]) - } - rm(i) - } - - if(use.cnv == T){ - - ext0 <- read.table(paste0(dir,filename,".cnv"),sep='',header=T,fill=T,na.strings =".",skip=1)%>% - dplyr::filter(ITERATION == -2000000000) - - }else{ - - ext0 <- ext00 %>% - dplyr::filter(ITERATION == -1000000000) %>% # NONMEM User Guide VIII for definition (final estimates) - dplyr::filter(dplyr::row_number() == max(dplyr::row_number())) - } - - tmpfixed <- ext00 %>% - dplyr::filter(ITERATION == -1000000006) %>% # NONMEM User Guide VIII for definition (fixed parameters) - dplyr::filter(dplyr::row_number() == max(dplyr::row_number())) - - if(sigdig > 0){ - omnofix <- tmpfixed[1,dplyr::starts_with("OMEGA", vars = colnames(tmpfixed))] - - if(class(omnofix)=="numeric"){ # 3/17/2024 fix load when only 1 IIV - omnofix <- data.frame("OMEGA.1.1." = omnofix) - } - - omnofix <- colnames(omnofix[which(omnofix[1,] != 1)]) - - if(length(omnofix)>0){ # 3/17/2024 fix load when all IIV fixed - tmpomnofix <- lapply(1:length(omnofix), function(i){ - nofixtmpa <- strsplit(trimws(omnofix[[i]]),"\\.") - return(data.frame(R = as.numeric(nofixtmpa[[1]][2]), C = as.numeric(nofixtmpa[[1]][3]))) - }) - omnofix <- dplyr::bind_rows(tmpomnofix) - }else{ - omnofix <- NULL - } - }else{ - omnofix <- NULL - } - - ext <- list(NITER = NA, OFV = NA, THETA = NA, OMEGA = NA) - - ext$NITER <- max(ext00$ITERATION) - ext$OFV <- ext0[1,which(substr(colnames(ext0),nchar(colnames(ext0))-2,nchar(ext0)) == "OBJ")] - ext$THETA <- ext0[1,dplyr::starts_with("THETA",vars = colnames(ext0))] - - tmpom0 <- ext0[1,dplyr::starts_with("OMEGA",vars = colnames(ext0))] - if(class(tmpom0)=="numeric"){ # 3/17/2024 fix load when only 1 IIV - tmpom0 <- data.frame("OMEGA.1.1." = tmpom0) - } - - tmpn <- strsplit(trimws(colnames(tmpom0)[ncol(tmpom0)]), "\\.") - tmpn <- as.numeric(tmpn[[1]][length(tmpn[[1]])]) - - tmpom2 <- matrix(data = 0, ncol = tmpn, nrow = tmpn) - colnames(tmpom2) <- paste0("OMEGA",1:tmpn) - rownames(tmpom2) <- paste0("OMEGA",1:tmpn) - - tmpom <- tmpom0[1, which(tmpom0 != 0)] - if(class(tmpom)=="numeric"){ # 3/17/2024 fix load when only 1 IIV - tmpom_val <- tmpom - tmpom <- data.frame() - tmpom[1,colnames(tmpom0)[which(tmpom0!=0)]] = tmpom_val - } - - if(length(tmpom)>0){ # 3/17/2024 fix error all IIV fixed to zero - for(i in 1:length(tmpom)){ - - tmp <- strsplit(trimws(colnames(tmpom)[i]),"\\.")[[1]] - tmpr <- as.numeric(tmp[2]) - tmpc <- as.numeric(tmp[3]) - - if(sigdig > 0 & !is.null(omnofix)){ # 3/17/2024 fix load when all iiv fixed - - omvalround <- tmpom[1,i] - - tmpa <- which(omnofix$R == tmpr) - - if(length(tmpa)>0){ - - tmpa <- omnofix[tmpa,] - tmpa <- which(tmpa$C == tmpc) - - if(length(tmpa)>0){ - - omvalround <- signif(tmpom[1,i], sigdig) - } - } - - tmpom2[tmpr,tmpc] <- omvalround - tmpom2[tmpc,tmpr] <- omvalround - - }else{ - - tmpom2[tmpr,tmpc] <- tmpom[1,i] - tmpom2[tmpc,tmpr] <- tmpom[1,i] - } - } - } - - ext$OMEGA <- tmpom2 - - if(sigdig > 0){ - - thnofix <- which(tmpfixed[1,dplyr::starts_with("THETA",vars = colnames(tmpfixed))] != 1) - - if(length(thnofix)>0){ - ext[["THETA"]][thnofix] <- signif(ext[["THETA"]][thnofix],sigdig) - } - } - - return(list(ext=ext,ext0=ext0)) -} - -## END #### +## Loading Nonmem Files #### + +## FUNCTION LOAD CTL #### + +#' Load NONMEM ctl file into R +#' +#' Loads the NONMEM ctl file into R for translation to mrgsolve format. +#' +#' @param filename String of the NONMEM model name without the .ctl extension +#' @param dir String of the directory path to the NONMEM run files +#' +#' @return R dataframe of the NONMEM ctl file +#' +#' @examples +#' # load_ctl(filename = "nonmem-model", dir = "path/to/directory/") +#' +#' @export +load_ctl <- function(filename = NULL, dir = ""){ + + ctl <- read.delim2(paste0(dir,filename,".ctl"), header = F) %>% + dplyr::mutate(V1 = trimws(V1, which = "both"))%>% # remove leading and trailing white space + dplyr::filter(substr(V1,1,1) != ";", V1 != "")%>% # remove white space or comment rows + dplyr::mutate(V1 = gsub(";.*","",V1))%>% # remove anything after comment + dplyr::mutate(FLG_BLOCK = ifelse(startsWith(V1, "$"), 1, 0))%>% # flag beginning of each block + dplyr::mutate(BLOCK = suppressWarnings(ifelse(FLG_BLOCK == 1, trimws(substr(V1,2,6), which = "both"), NA)))%>% # get block name + dplyr::mutate(BLOCK = zoo::na.locf(BLOCK, na.rm = F, fromLast = F)) # pull block name down until next block starts + + return(ctl) +} + +## FUNCTION LOAD EXT #### + +#' Load NONMEM ext file into R +#' +#' Loads the NONMEM ext file into R for capture of the final estimates. +#' +#' @param filename String of the NONMEM model name without the .ext extension +#' @param dir String of the directory path to the NONMEM run files +#' @param sigdig Numeric of the number of significant digits to round non-fixed thetas and etas to; -1 for no rounding +#' @param use.cnv Logical for whether to use the NONMEM cnv file for final parameter estimates instead of the ext file (\code{T} or \code{F}) +#' +#' @return R list of the NONMEM final OFV, parameter estimates, and IIV magnitudes +#' +#' @examples +#' load_ext(filename = "nonmem-model", dir = "path/to/directory/") +#' +#' @export +load_ext <- function(filename = NULL, dir = "", sigdig = -1, use.cnv = F){ + + ext00 <- read.table(paste0(dir,filename,".ext"),sep='',header=T,fill=T,na.strings=".", skip=1) + + if(class(ext00$ITERATION) != "numeric"){ + for(i in 1:ncol(ext00)){ + ext00[,i] <- as.numeric(ext00[,i]) + } + rm(i) + } + + if(use.cnv == T){ + + ext0 <- read.table(paste0(dir,filename,".cnv"),sep='',header=T,fill=T,na.strings =".",skip=1)%>% + dplyr::filter(ITERATION == -2000000000) + + }else{ + + ext0 <- ext00 %>% + dplyr::filter(ITERATION == -1000000000) %>% # NONMEM User Guide VIII for definition (final estimates) + dplyr::filter(dplyr::row_number() == max(dplyr::row_number())) + } + + tmpfixed <- ext00 %>% + dplyr::filter(ITERATION == -1000000006) %>% # NONMEM User Guide VIII for definition (fixed parameters) + dplyr::filter(dplyr::row_number() == max(dplyr::row_number())) + + if(sigdig > 0){ + omnofix <- tmpfixed[1,dplyr::starts_with("OMEGA", vars = colnames(tmpfixed))] + + if(class(omnofix)=="numeric"){ # 3/17/2024 fix load when only 1 IIV + omnofix <- data.frame("OMEGA.1.1." = omnofix) + } + + omnofix <- colnames(omnofix[which(omnofix[1,] != 1)]) + + if(length(omnofix)>0){ # 3/17/2024 fix load when all IIV fixed + tmpomnofix <- lapply(1:length(omnofix), function(i){ + nofixtmpa <- strsplit(trimws(omnofix[[i]]),"\\.") + return(data.frame(R = as.numeric(nofixtmpa[[1]][2]), C = as.numeric(nofixtmpa[[1]][3]))) + }) + omnofix <- dplyr::bind_rows(tmpomnofix) + }else{ + omnofix <- NULL + } + }else{ + omnofix <- NULL + } + + ext <- list(NITER = NA, OFV = NA, THETA = NA, OMEGA = NA) + + ext$NITER <- max(ext00$ITERATION) + ext$OFV <- ext0[1,which(substr(colnames(ext0),nchar(colnames(ext0))-2,nchar(ext0)) == "OBJ")] + ext$THETA <- ext0[1,dplyr::starts_with("THETA",vars = colnames(ext0))] + + tmpom0 <- ext0[1,dplyr::starts_with("OMEGA",vars = colnames(ext0))] + if(class(tmpom0)=="numeric"){ # 3/17/2024 fix load when only 1 IIV + tmpom0 <- data.frame("OMEGA.1.1." = tmpom0) + } + + tmpn <- strsplit(trimws(colnames(tmpom0)[ncol(tmpom0)]), "\\.") + tmpn <- as.numeric(tmpn[[1]][length(tmpn[[1]])]) + + tmpom2 <- matrix(data = 0, ncol = tmpn, nrow = tmpn) + colnames(tmpom2) <- paste0("OMEGA",1:tmpn) + rownames(tmpom2) <- paste0("OMEGA",1:tmpn) + + tmpom <- tmpom0[1, which(tmpom0 != 0)] + if(class(tmpom)=="numeric"){ # 3/17/2024 fix load when only 1 IIV + tmpom_val <- tmpom + tmpom <- data.frame() + tmpom[1,colnames(tmpom0)[which(tmpom0!=0)]] = tmpom_val + } + + if(length(tmpom)>0){ # 3/17/2024 fix error all IIV fixed to zero + for(i in 1:length(tmpom)){ + + tmp <- strsplit(trimws(colnames(tmpom)[i]),"\\.")[[1]] + tmpr <- as.numeric(tmp[2]) + tmpc <- as.numeric(tmp[3]) + + if(sigdig > 0 & !is.null(omnofix)){ # 3/17/2024 fix load when all iiv fixed + + omvalround <- tmpom[1,i] + + tmpa <- which(omnofix$R == tmpr) + + if(length(tmpa)>0){ + + tmpa <- omnofix[tmpa,] + tmpa <- which(tmpa$C == tmpc) + + if(length(tmpa)>0){ + + omvalround <- signif(tmpom[1,i], sigdig) + } + } + + tmpom2[tmpr,tmpc] <- omvalround + tmpom2[tmpc,tmpr] <- omvalround + + }else{ + + tmpom2[tmpr,tmpc] <- tmpom[1,i] + tmpom2[tmpc,tmpr] <- tmpom[1,i] + } + } + } + + ext$OMEGA <- tmpom2 + + if(sigdig > 0){ + + thnofix <- which(tmpfixed[1,dplyr::starts_with("THETA",vars = colnames(tmpfixed))] != 1) + + if(length(thnofix)>0){ + ext[["THETA"]][thnofix] <- signif(ext[["THETA"]][thnofix],sigdig) + } + } + + return(list(ext=ext,ext0=ext0)) +} + +## END #### diff --git a/R/nonmem2mrgsolve.R b/R/nonmem2mrgsolve.R index 74a04fc..b001f88 100644 --- a/R/nonmem2mrgsolve.R +++ b/R/nonmem2mrgsolve.R @@ -1,82 +1,82 @@ -## FUNCTION MASTER #### - -#' Automated NONMEM to mrgsolve Translation -#' -#' Translates a NONMEM model into mrgsolve syntax using the NONMEM ctl and ext (or cnv) files. -#' -#' @param filename String of the NONMEM model name with or without the .ctl extension -#' @param dir String of the directory path to the NONMEM files (if not already given in the filename input; or if the working directory was not already set) -#' @param sigdig Numeric of the number of significant digits to round non-fixed thetas and etas to; default NULL for no rounding -#' @param write Logical for whether to write the mrgsolve code to an R file (\code{T} or \code{F}) -#' @param return.orig Logical for whether to output the original NONMEM ctl and ext files (\code{T} or \code{F}) -#' @param out.filename String of the name for the mrgsolve output file without the .R extension -#' @param use.cnv Logical for whether to use the NONMEM cnv file for final parameter estimates instead of the ext file (\code{T} or \code{F}) -#' -#' @return R dataframe of the mrgsolve code -#' -#' @examples -#' setwd("path/to/directory") -#' nonmem2mrgsolve::nonmem2mrgsolve(filename = "nonmem-model.ctl") -#' -#' @export -nonmem2mrgsolve <- function(filename = NULL, dir = NULL, sigdig = NULL, write = T, return.orig = F, out.filename = NULL, use.cnv = F){ - - keep_block <- c("PROB", "PROBL", "PROBLEM", "INPUT", "MODEL", "PK", "DES", "TABLE") - - in.filename <- gsub(".ctl","",filename) - - tsigdig <- ifelse(!is.null(sigdig), sigdig, -1) - tdir <- ifelse(!is.null(dir), paste0(dir,"/"), "") - tusecnv <- ifelse(use.cnv == T, T, F) - - btemp <- load_ext(in.filename, tdir, sigdig = tsigdig, use.cnv = tusecnv) - - ext0 <- btemp$ext0 - ext <- btemp$ext - - ctl0 <- load_ctl(in.filename, tdir) - - ctl <- ctl0 %>% - dplyr::filter(BLOCK %in% keep_block) # filter to useful blocks - - btemp <- get_block_input(ctl,ext) - params <- btemp$params - mrg_code <- btemp$mrg_code - - btemp <- get_block_model(ctl, mrg_code) - mrg_code <- btemp$mrg_code - cmts <- btemp$cmts - - btemp <- get_block_pk(ctl, mrg_code, cmts) - mrg_code <- btemp$mrg_code - params2 <- btemp$params2 - - mrg_code <- get_block_omega(ext0 = ext, mrg_code = mrg_code) - - all_params <- sort(c(params$V1,params2)) - mrg_code <- get_block_table(ctl, mrg_code, all_params, cmts$V1) - - if(write == T){ - - outfile <- paste0("mrgsolve-code-V0_",in.filename) - - if(!is.null(out.filename)){ - if(!is.na(out.filename) & out.filename != "" & out.filename != " "){ - outfile <- out.filename - } - } - - writemrgsolve(mrg_code, outfile, dir = dir) - } - - if(return.orig == T){ - - return(list(mrg_code=mrg_code,ctl0=ctl0,ext0=ext0,ext=ext)) - - }else{ - - return(mrg_code) - } -} - -## END #### +## FUNCTION MASTER #### + +#' Automated NONMEM to mrgsolve Translation +#' +#' Translates a NONMEM model into mrgsolve syntax using the NONMEM ctl and ext (or cnv) files. +#' +#' @param filename String of the NONMEM model name with or without the .ctl extension +#' @param dir String of the directory path to the NONMEM files (if not already given in the filename input; or if the working directory was not already set) +#' @param sigdig Numeric of the number of significant digits to round non-fixed thetas and etas to; default NULL for no rounding +#' @param write Logical for whether to write the mrgsolve code to an R file (\code{T} or \code{F}) +#' @param return.orig Logical for whether to output the original NONMEM ctl and ext files (\code{T} or \code{F}) +#' @param out.filename String of the name for the mrgsolve output file without the .R extension +#' @param use.cnv Logical for whether to use the NONMEM cnv file for final parameter estimates instead of the ext file (\code{T} or \code{F}) +#' +#' @return R dataframe of the mrgsolve code +#' +#' @examples +#' # setwd("path/to/directory") +#' # nonmem2mrgsolve::nonmem2mrgsolve(filename = "nonmem-model.ctl") +#' +#' @export +nonmem2mrgsolve <- function(filename = NULL, dir = NULL, sigdig = NULL, write = T, return.orig = F, out.filename = NULL, use.cnv = F){ + + keep_block <- c("PROB", "PROBL", "PROBLEM", "INPUT", "MODEL", "PK", "DES", "TABLE") + + in.filename <- gsub(".ctl","",filename) + + tsigdig <- ifelse(!is.null(sigdig), sigdig, -1) + tdir <- ifelse(!is.null(dir), paste0(dir,"/"), "") + tusecnv <- ifelse(use.cnv == T, T, F) + + btemp <- load_ext(in.filename, tdir, sigdig = tsigdig, use.cnv = tusecnv) + + ext0 <- btemp$ext0 + ext <- btemp$ext + + ctl0 <- load_ctl(in.filename, tdir) + + ctl <- ctl0 %>% + dplyr::filter(BLOCK %in% keep_block) # filter to useful blocks + + btemp <- get_block_input(ctl,ext) + params <- btemp$params + mrg_code <- btemp$mrg_code + + btemp <- get_block_model(ctl, mrg_code) + mrg_code <- btemp$mrg_code + cmts <- btemp$cmts + + btemp <- get_block_pk(ctl, mrg_code, cmts) + mrg_code <- btemp$mrg_code + params2 <- btemp$params2 + + mrg_code <- get_block_omega(ext0 = ext, mrg_code = mrg_code) + + all_params <- sort(c(params$V1,params2)) + mrg_code <- get_block_table(ctl, mrg_code, all_params, cmts$V1) + + if(write == T){ + + outfile <- paste0("mrgsolve-code-V0_",in.filename) + + if(!is.null(out.filename)){ + if(!is.na(out.filename) & out.filename != "" & out.filename != " "){ + outfile <- out.filename + } + } + + writemrgsolve(mrg_code, outfile, dir = dir) + } + + if(return.orig == T){ + + return(list(mrg_code=mrg_code,ctl0=ctl0,ext0=ext0,ext=ext)) + + }else{ + + return(mrg_code) + } +} + +## END #### diff --git a/R/writemrgsolve.R b/R/writemrgsolve.R index baf7ddd..0e51f1e 100644 --- a/R/writemrgsolve.R +++ b/R/writemrgsolve.R @@ -1,35 +1,35 @@ -## FUNCTION WRITE MRGSOLVE #### - -#' Write the mrgsolve code to an R file -#' -#' Writes the mrgsolve code, translated from the input NONMEM run, to an R file. -#' -#' @param mrg_code Dataframe of the NONMEM model translated into mrgsolve code -#' @param filename String of the name for the mrgsolve output file without the .R extension -#' @param dir String of the directory path to the NONMEM run files -#' -#' @return R file of the mrgsolve code -#' -#' @examples -#' writemrgsolve() -#' -#' @export -writemrgsolve <- function(mrg_code = NULL, filename = "mrgsolve_code0", dir = NULL){ - - tdir <- ifelse(is.na(dir) | is.null(dir), "", paste0(dir,"/")) - nme_pth <- paste0(tdir,filename,".R") - - file <- file(nme_pth) - - cat("code <- ' ",file=nme_pth,sep="\n\n") - - for(i in 1:nrow(mrg_code)){ - cat(mrg_code[i,"V1"],file=nme_pth,sep = "\n",append=TRUE) - } - - cat("'",file=nme_pth,append = T) - - close(file) -} - -## END #### +## FUNCTION WRITE MRGSOLVE #### + +#' Write the mrgsolve code to an R file +#' +#' Writes the mrgsolve code, translated from the input NONMEM run, to an R file. +#' +#' @param mrg_code Dataframe of the NONMEM model translated into mrgsolve code +#' @param filename String of the name for the mrgsolve output file without the .R extension +#' @param dir String of the directory path to the NONMEM run files +#' +#' @return R file of the mrgsolve code +#' +#' @examples +#' # writemrgsolve() +#' +#' @export +writemrgsolve <- function(mrg_code = NULL, filename = "mrgsolve_code0", dir = NULL){ + + tdir <- ifelse(is.na(dir) | is.null(dir), "", paste0(dir,"/")) + nme_pth <- paste0(tdir,filename,".R") + + file <- file(nme_pth) + + cat("code <- ' ",file=nme_pth,sep="\n\n") + + for(i in 1:nrow(mrg_code)){ + cat(mrg_code[i,"V1"],file=nme_pth,sep = "\n",append=TRUE) + } + + cat("'",file=nme_pth,append = T) + + close(file) +} + +## END #### diff --git a/README.Rmd b/README.Rmd index 4af44af..ce998ae 100644 --- a/README.Rmd +++ b/README.Rmd @@ -13,7 +13,7 @@ Provide an R package that automates NONMEM to mrgsolve translation to reduce hum ## Introduction -Pharmacometricians often utilize multiple software, with NONMEM (ICON plc, Dublin, Ireland) widely regarded as the current gold standard for population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) modeling. While NONMEM has the ability to simulate, it is often more convenient and practical to perform simulations using free open-source software such as R which can also perform post-processing of the output.A popular pharmacometrics-orientated R package for solving ODE systems is mrgsolve. Although mrgsolve has built-in functionality to streamline translation, to the best of our knowledge a previously-developed and publicly-available R package for fully automated NONMEM to mrgsolve translation does not exist. +Pharmacometricians often utilize multiple software, with NONMEM (ICON plc, Dublin, Ireland) widely regarded as the current gold standard for population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) modeling. While NONMEM has the ability to simulate, it is often more convenient and practical to perform simulations using free open-source software such as R which can also perform post-processing of the output. A popular pharmacometrics-orientated R package for solving ODE systems is mrgsolve. Although mrgsolve has built-in functionality to streamline translation, to the best of our knowledge a previously-developed and publicly-available R package for fully automated NONMEM to mrgsolve translation does not exist. ## Installation @@ -24,7 +24,7 @@ devtools::install_github("Andy00000000000/nonmem2mrgsolve") ## Getting Started -Full work-through examples will be created shortly, but in the meantime assume that a NONMEM run has finished estimating and has explicitly-defined ODEs. The ctl and ext files are both named pbpk-101 and are located at C:/Documents/NONMEM/Project. +As an orientation, assume that a theoretical NONMEM run has finished estimating and has explicitly-defined ODEs. The ctl and ext files are both named pbpk-101 and are located at C:/Documents/NONMEM/Project. Load R and run: ```{r} @@ -35,7 +35,7 @@ nonmem2mrgsolve("pbpk-101") # run the nonmem2mrgsolve function with def The resulting mrgsolve code will be wrote to mrgsolve-code-V0_pbpk-101.R within the C:/Documents/NONMEM/Project folder. The user should then validate the translation, for which there is an intuitive and established framework [(Here)](https://mrgsolve.org/blog/posts/2023-update-validation.html). -## Usage Statement +## Usage Statement {.unnumbered #link_1} ```{r} nonmem2mrgsolve::nonmem2mrgsolve( @@ -60,3 +60,108 @@ Please feel free to report problems using the [Issue Tracker](https://github.com [Finch Studio](https://finchstudio.io/) is an integrated modeling environment for pharmacometricians, clinical pharmacologists, and other team members to visualize, develop, and organize PK/PD models and data. It includes a modern NONMEM code editor and workbench, interactive data tables and visualizations, and a PK/PD model library. The development team is led by [Dr. Mohamed Ismail](https://www.linkedin.com/in/mohamed-ismail-bb54a367/). nonmem2mrgsolve was developed at ePD by [Andrew Santulli](https://www.linkedin.com/in/andrew-santulli-219034156/). + +## Vignette + +Three case study models are provided within the vignette folder. The following section will use these examples to provide a brief tutorial on how to implement nonmem2mrgsolve into the model development and simulation workflow. To get started, download nonmem2mrgsolve and copy the vignette folder to a convenient file location. + +### Example 1: A 1-compartment model with first-order absorption {.unnumbered #link_2} + +Within the vignette >> models directory, you should find three folders: + +![](readme_images/vignette_01.png){width=40%} + +This first example is drugx-oral-1cmt-101, in which you will find the NONMEM control stream (.ctl) and output files (.ext and .lst). The nonmem2mrgsolve package does not require the .lst file, it is provided solely for user reference. The nonmem2mrgsolve-translated mrgsolve code, along with the mrgsolve code following any necessary user modifications, are provided as well for reference, but could be deleted at this step and recreated during the vignette. The run_nonmem2mrgsolve_drugx.R file contains all the code presented for this example of the vignette. + +![](readme_images/vignette_02.png){width=40%} + +Now that the directory structure is clear, start R, load the nonmem2mrgsolve package, and set the working directory to immediately before entering the vignette folder: +```{r} +library("nonmem2mrgsolve") +setwd("Your file path to vignette folder here") +``` + +Translating the NONMEM model into mrgsolve code is accomplished using a single function call: +```{r} +nonmem2mrgsolve( + "mod1.ctl", # the NONMEM run name + "./vignette/models/drugx-oral-1cmt-101/", # path to mod1.ctl and mod1.ext, from the working directory (which was set earlier) + out.filename = "mrgsolve_code_drugx-oral", # name for the mrgsolve code .R output file + sigdig = 3 # number of significant digits to report thetas and omegas to within the mrgsolve code (optional) +) +``` +During the translation, the final parameter estimates (thetas and omegas) are obtained from the NONMEM .ext file, while the parameter and differential equations are pulled from the NONMEM .ctl file. There are several optional inputs to the nonmem2mrgsolve function, as detailed in the [usage statement](#link_1). + +When the translation is finished, the mrgsolve code will print to the R console and will also be written to a .R file: + +![](readme_images/vignette_03.png){width=100%} +![](readme_images/vignette_04.png){width=40%} + + +Now is a good time to check whether the nonmem2mrgsolve-translated mrgsolve code requires any user modifications in order to compile: +```{r} +source("./vignettes/models/drugx-oral-1cmt-101/mrgsolve_code_drugx-oral.R") +mrgsolve::mcode("Test_Unmodified_Translation",code) +``` + +In this example manual user changes to the mrgsolve code are not needed, since the model successfully compiled: + +![](readme_images/vignette_05.png){width=50%} + + +If certain model complexities are present (such as time-varying covariates), the nonmem2mrgsolve-translated mrgsolve code may fail to compile into an mrgsolve model object. The compilation failure will provide informative error messages for locating the line of code that needs attention. The compilation failure will also prevent the user from running simulations without first addressing problems in the code. + +As a final step before conducting simulations, the user should validate the mrgsolve model. There is an intuitive and established framework [(Here)](https://mrgsolve.org/blog/posts/2023-update-validation.html). Model validation remains the responsibility of the user and should always be performed, regardless of the robustness of the translation software or the experience of the user. + +### Example 2: A QSS Target-Mediated Drug Disposition (TMDD) Model and Indirect Response PK-PD Model + +This example is located within the evolocumab-tmdd-qss-pkpd-101 folder of the vignette >> models directory. Since the steps for translating the NONMEM model into mrgsolve code are equivalent to those presented in [Example 1](#link_2), the tutorial for this case study will start at compiling the nonmem2mrgsolve-translated mrgsolve code into an mrgsolve model object. The complete code for running the earlier steps as well is included within the run_nonmem2mrgsolve_evolocumab.R file. + +Attempting to compile the nonmem2mrgsolve-translated mrgsolve code results in a fatal error: +```{r} +source("./vignette/models/evolocumab-tmdd-qss-pkpd-101/mrgsolve_code_evolocumab-tmdd.R") +mrgsolve::mcode("Test_Unmodified_Translation",code) +``` +![](readme_images/vignette_06.png){width=100%} + + +From the error message it is clear that the issue occurred when the NONMEM dataset column "TIME" was being used in the differential equation code block ($DES). Mrgsolve syntax requires this to be labeled as "SOLVERTIME". + +The user can manually make this single change while leaving the rest of the nonmem2mrgsolve code unmodified: + +![](readme_images/vignette_07.png){width=100%} + + +Compiling the corrected mrgsolve code is successful: +```{r} +source("./vignette/models/evolocumab-tmdd-qss-pkpd-101/mrgsolve_code_evolocumab-tmdd_user-modified.R") +mrgsolve::mcode("Test_Modified_Translation",code) +``` +![](readme_images/vignette_08.png){width=50%} + +### Example 3: A Whole-body Physiologically-based Pharmacokinetic (PBPK) Model + +This example is located within the mavoglurant-pbpk-101 folder of the vignette >> models directory. Since the steps for translating the NONMEM model into mrgsolve code are equivalent to those presented in [Example 1](#link_2), the tutorial for this case study will start at compiling the nonmem2mrgsolve-translated mrgsolve code into an mrgsolve model object. The complete code for running the earlier steps as well is included within the run_nonmem2mrgsolve_mavoglurant.R file. + +Attempting to compile the nonmem2mrgsolve-translated mrgsolve code results in a fatal error: +```{r} +source("./vignette/models/mavoglurant-pbpk-101/mrgsolve_code_mavoglurant-pbpk.R") +mrgsolve::mcode("Test_Unmodified_Translation",code) +``` +![](readme_images/vignette_09.png){width=80%} + + +From the error message it is clear that the issue occurred because "RATE" was not declared in the parameter block ($PARAM). Additionally, this should be renamed since "RATE" is a reserved term. + +The user can manually make these two changes while leaving the rest of the nonmem2mrgsolve code unmodified: + +![](readme_images/vignette_10.png){width=100%} +![](readme_images/vignette_11.png){width=100%} + + +Compiling the corrected mrgsolve code is successful: +```{r} +source("./vignette/models/mavoglurant-pbpk-101/mrgsolve_code_mavoglurant-pbpk_user-modified.R") +mrgsolve::mcode("Test_Modified_Translation",code) +``` +![](readme_images/vignette_12.png){width=50%} diff --git a/README.md b/README.md index be4d931..a949c4a 100644 --- a/README.md +++ b/README.md @@ -14,7 +14,7 @@ population pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) modeling. While NONMEM has the ability to simulate, it is often more convenient and practical to perform simulations using free open-source software such as R which can also perform post-processing of -the output.A popular pharmacometrics-orientated R package for solving +the output. A popular pharmacometrics-orientated R package for solving ODE systems is mrgsolve. Although mrgsolve has built-in functionality to streamline translation, to the best of our knowledge a previously-developed and publicly-available R package for fully @@ -31,10 +31,9 @@ devtools::install_github("Andy00000000000/nonmem2mrgsolve") ## Getting Started -Full work-through examples will be created shortly, but in the meantime -assume that a NONMEM run has finished estimating and has -explicitly-defined ODEs. The ctl and ext files are both named pbpk-101 -and are located at C:/Documents/NONMEM/Project. +As an orientation, assume that a theoretical NONMEM run has finished +estimating and has explicitly-defined ODEs. The ctl and ext files are +both named pbpk-101 and are located at C:/Documents/NONMEM/Project. Load R and run: @@ -91,3 +90,167 @@ Ismail](https://www.linkedin.com/in/mohamed-ismail-bb54a367/). nonmem2mrgsolve was developed at ePD by [Andrew Santulli](https://www.linkedin.com/in/andrew-santulli-219034156/). + +## Vignette + +Three case study models are provided within the vignette folder. The +following section will use these examples to provide a brief tutorial on +how to implement nonmem2mrgsolve into the model development and +simulation workflow. To get started, download nonmem2mrgsolve and copy +the vignette folder to a convenient file location. + +### Example 1: A 1-compartment model with first-order absorption + +Within the vignette >> models directory, you should find three +folders: + + + +This first example is drugx-oral-1cmt-101, in which you will find the +NONMEM control stream (.ctl) and output files (.ext and .lst). The +nonmem2mrgsolve package does not require the .lst file, it is provided +solely for user reference. The nonmem2mrgsolve-translated mrgsolve code, +along with the mrgsolve code following any necessary user modifications, +are provided as well for reference, but could be deleted at this step +and recreated during the vignette. The run\_nonmem2mrgsolve\_drugx.R +file contains all the code presented for this example of the vignette. + + + +Now that the directory structure is clear, start R, load the +nonmem2mrgsolve package, and set the working directory to immediately +before entering the vignette folder: + +``` r +library("nonmem2mrgsolve") +setwd("Your file path to vignette folder here") +``` + +Translating the NONMEM model into mrgsolve code is accomplished using a +single function call: + +``` r +nonmem2mrgsolve( + "mod1.ctl", # the NONMEM run name + "./vignette/models/drugx-oral-1cmt-101/", # path to mod1.ctl and mod1.ext, from the working directory (which was set earlier) + out.filename = "mrgsolve_code_drugx-oral", # name for the mrgsolve code .R output file + sigdig = 3 # number of significant digits to report thetas and omegas to within the mrgsolve code (optional) +) +``` + +During the translation, the final parameter estimates (thetas and +omegas) are obtained from the NONMEM .ext file, while the parameter and +differential equations are pulled from the NONMEM .ctl file. There are +several optional inputs to the nonmem2mrgsolve function, as detailed in +the [usage statement](#link_1). + +When the translation is finished, the mrgsolve code will print to the R +console and will also be written to a .R file: + + + + +Now is a good time to check whether the nonmem2mrgsolve-translated +mrgsolve code requires any user modifications in order to compile: + +``` r +source("./vignettes/models/drugx-oral-1cmt-101/mrgsolve_code_drugx-oral.R") +mrgsolve::mcode("Test_Unmodified_Translation",code) +``` + +In this example manual user changes to the mrgsolve code are not needed, +since the model successfully compiled: + + + +If certain model complexities are present (such as time-varying +covariates), the nonmem2mrgsolve-translated mrgsolve code may fail to +compile into an mrgsolve model object. The compilation failure will +provide informative error messages for locating the line of code that +needs attention. The compilation failure will also prevent the user from +running simulations without first addressing problems in the code. + +As a final step before conducting simulations, the user should validate +the mrgsolve model. There is an intuitive and established framework +[(Here)](https://mrgsolve.org/blog/posts/2023-update-validation.html). +Model validation remains the responsibility of the user and should +always be performed, regardless of the robustness of the translation +software or the experience of the user. + +### Example 2: A QSS Target-Mediated Drug Disposition (TMDD) Model and Indirect Response PK-PD Model + +This example is located within the evolocumab-tmdd-qss-pkpd-101 folder +of the vignette >> models directory. Since the steps for +translating the NONMEM model into mrgsolve code are equivalent to those +presented in [Example 1](#link_2), the tutorial for this case study will +start at compiling the nonmem2mrgsolve-translated mrgsolve code into an +mrgsolve model object. The complete code for running the earlier steps +as well is included within the run\_nonmem2mrgsolve\_evolocumab.R file. + +Attempting to compile the nonmem2mrgsolve-translated mrgsolve code +results in a fatal error: + +``` r +source("./vignette/models/evolocumab-tmdd-qss-pkpd-101/mrgsolve_code_evolocumab-tmdd.R") +mrgsolve::mcode("Test_Unmodified_Translation",code) +``` + + + +From the error message it is clear that the issue occurred when the +NONMEM dataset column “TIME” was being used in the differential equation +code block ($DES). Mrgsolve syntax requires this to be labeled as +“SOLVERTIME”. + +The user can manually make this single change while leaving the rest of +the nonmem2mrgsolve code unmodified: + + + +Compiling the corrected mrgsolve code is successful: + +``` r +source("./vignette/models/evolocumab-tmdd-qss-pkpd-101/mrgsolve_code_evolocumab-tmdd_user-modified.R") +mrgsolve::mcode("Test_Modified_Translation",code) +``` + + + +### Example 3: A Whole-body Physiologically-based Pharmacokinetic (PBPK) Model + +This example is located within the mavoglurant-pbpk-101 folder of the +vignette >> models directory. Since the steps for translating the +NONMEM model into mrgsolve code are equivalent to those presented in +[Example 1](#link_2), the tutorial for this case study will start at +compiling the nonmem2mrgsolve-translated mrgsolve code into an mrgsolve +model object. The complete code for running the earlier steps as well is +included within the run\_nonmem2mrgsolve\_mavoglurant.R file. + +Attempting to compile the nonmem2mrgsolve-translated mrgsolve code +results in a fatal error: + +``` r +source("./vignette/models/mavoglurant-pbpk-101/mrgsolve_code_mavoglurant-pbpk.R") +mrgsolve::mcode("Test_Unmodified_Translation",code) +``` + + + +From the error message it is clear that the issue occurred because +“RATE” was not declared in the parameter block ($PARAM). Additionally, +this should be renamed since “RATE” is a reserved term. + +The user can manually make these two changes while leaving the rest of +the nonmem2mrgsolve code unmodified: + + + + +Compiling the corrected mrgsolve code is successful: + +``` r +source("./vignette/models/mavoglurant-pbpk-101/mrgsolve_code_mavoglurant-pbpk_user-modified.R") +mrgsolve::mcode("Test_Modified_Translation",code) +``` + + diff --git a/readme_images/vignette_01.PNG b/readme_images/vignette_01.PNG new file mode 100644 index 0000000..60cec14 Binary files /dev/null and b/readme_images/vignette_01.PNG differ diff --git a/readme_images/vignette_02.PNG b/readme_images/vignette_02.PNG new file mode 100644 index 0000000..5d3f526 Binary files /dev/null and b/readme_images/vignette_02.PNG differ diff --git a/readme_images/vignette_03.PNG b/readme_images/vignette_03.PNG new file mode 100644 index 0000000..150f1ff Binary files /dev/null and b/readme_images/vignette_03.PNG differ diff --git a/readme_images/vignette_04.PNG b/readme_images/vignette_04.PNG new file mode 100644 index 0000000..77f31fc Binary files /dev/null and b/readme_images/vignette_04.PNG differ diff --git a/readme_images/vignette_05.PNG b/readme_images/vignette_05.PNG new file mode 100644 index 0000000..e1ffa71 Binary files /dev/null and b/readme_images/vignette_05.PNG differ diff --git a/readme_images/vignette_06.PNG b/readme_images/vignette_06.PNG new file mode 100644 index 0000000..6a99d43 Binary files /dev/null and b/readme_images/vignette_06.PNG differ diff --git a/readme_images/vignette_07.PNG b/readme_images/vignette_07.PNG new file mode 100644 index 0000000..2082651 Binary files /dev/null and b/readme_images/vignette_07.PNG differ diff --git a/readme_images/vignette_08.PNG b/readme_images/vignette_08.PNG new file mode 100644 index 0000000..e3bf62b Binary files /dev/null and b/readme_images/vignette_08.PNG differ diff --git a/readme_images/vignette_09.PNG b/readme_images/vignette_09.PNG new file mode 100644 index 0000000..57ab1a3 Binary files /dev/null and b/readme_images/vignette_09.PNG differ diff --git a/readme_images/vignette_10.PNG b/readme_images/vignette_10.PNG new file mode 100644 index 0000000..0349aea Binary files /dev/null and b/readme_images/vignette_10.PNG differ diff --git a/readme_images/vignette_11.PNG b/readme_images/vignette_11.PNG new file mode 100644 index 0000000..2b6aaf9 Binary files /dev/null and b/readme_images/vignette_11.PNG differ diff --git a/readme_images/vignette_12.PNG b/readme_images/vignette_12.PNG new file mode 100644 index 0000000..0875ea0 Binary files /dev/null and b/readme_images/vignette_12.PNG differ diff --git a/vignette/models/drugx-oral-1cmt-101/mod1.ctl b/vignette/models/drugx-oral-1cmt-101/mod1.ctl new file mode 100644 index 0000000..e2531b0 --- /dev/null +++ b/vignette/models/drugx-oral-1cmt-101/mod1.ctl @@ -0,0 +1,60 @@ +$PROB ev_no-delay_first-order_one-compartment_linear + +$INPUT ID TIME EVID AMT DV RACEN WTKG Race=DROP + +$DATA "../../data/F1003-Asian-PK-Study.csv" IGNORE=@ + +$SUBROUTINES ADVAN13 TRANS1 TOL=9 SUBROUTINES=D + +$MODEL +COMP=(DEPOT,DEFDOSE) +COMP=(CENTRAL,DEFOBS) + +$PK + +TVKA = THETA(1) +KA = TVKA + +TVCL = THETA(2)*(WTKG/71.0)**THETA(4) +CL = TVCL*EXP(ETA(1)) + +TVV = THETA(3)*(WTKG/71.0)**THETA(5) +V = TVV*EXP(ETA(2)) +S2 = V + +$DES + +DADT(1) = -KA*A(1) +DADT(2) = KA*A(1) - (CL/V)*A(2) + +$ERROR + +IPRED = F +IRES = DV-IPRED +W = SQRT(IPRED**2*SIGMA(1,1)) +IWRES = IRES/W +Y = F + F*EPS(1) + +$THETA +(0, 0.783) ; KA ; 1/hr ; Absorption Rate Constant +(0, 17.3) ; CL ; L/hr ; Clearance +(0, 84.0) ; V ; L ; Volume of Distribution +(1.83) ; WTonCL +(1) ; WTonV + +$OMEGA BLOCK(2) +0.0103 ; CL +0.00 0.111 ; V + +$SIGMA +0.0206 ; Proportional + +$ESTIMATION METHOD=1 INTER NOABORT MAXEVAL=9999 PRINT=5 NSIG=3 SIGL=9 NOTHETABOUNDTEST +NOOMEGABOUNDTEST NOSIGMABOUNDTEST + +$COVARIANCE PRINT=E UNCONDITIONAL + +$TABLE ID TIME DV MDV EVID IPRED CWRES IWRES ONEHEADER NOPRINT FILE=sdtab1 +$TABLE ID KA CL V ETAS(1:LAST) ONEHEADER NOPRINT FILE=patab1 ; model parameters +$TABLE ID RACEN ONEHEADER NOPRINT FILE=catab1 ; categorical covariates +$TABLE ID WTKG ONEHEADER NOPRINT FILE=cotab1 ; continuous covariates \ No newline at end of file diff --git a/vignette/models/drugx-oral-1cmt-101/mod1.ext b/vignette/models/drugx-oral-1cmt-101/mod1.ext new file mode 100644 index 0000000..df1ba85 --- /dev/null +++ b/vignette/models/drugx-oral-1cmt-101/mod1.ext @@ -0,0 +1,16 @@ +TABLE NO. 1: First Order Conditional Estimation with Interaction: Goal Function=MINIMUM VALUE OF OBJECTIVE FUNCTION: Problem=1 Subproblem=0 Superproblem1=0 Iteration1=0 Superproblem2=0 Iteration2=0 + ITERATION THETA1 THETA2 THETA3 THETA4 THETA5 SIGMA(1,1) OMEGA(1,1) OMEGA(2,1) OMEGA(2,2) OBJ + 0 7.83000E-01 1.73000E+01 8.40000E+01 1.83000E+00 1.00000E+00 2.06000E-02 1.03000E-02 0.00000E+00 1.11000E-01 -6481.6169580283204 + 5 8.24248E-01 1.73750E+01 8.96435E+01 1.94188E+00 2.10747E+00 2.06426E-02 1.04061E-02 0.00000E+00 1.60329E-02 -6548.9249358333400 + 10 7.92543E-01 1.73453E+01 8.52719E+01 1.90968E+00 1.56732E+00 2.04539E-02 8.74251E-03 0.00000E+00 6.86312E-03 -6639.5236031714330 + 15 7.82387E-01 1.73376E+01 8.58244E+01 1.85049E+00 1.58069E+00 2.05904E-02 1.04557E-02 0.00000E+00 7.65757E-03 -6645.4469074892349 + 20 7.82421E-01 1.73383E+01 8.58298E+01 1.85120E+00 1.58107E+00 2.05894E-02 1.04605E-02 0.00000E+00 7.64910E-03 -6645.4473027426147 + -1000000000 7.82421E-01 1.73383E+01 8.58298E+01 1.85120E+00 1.58107E+00 2.05894E-02 1.04605E-02 0.00000E+00 7.64910E-03 -6645.4473027426147 + -1000000001 9.55997E-03 1.93321E-01 9.54265E-01 5.61044E-02 5.84250E-02 7.76336E-04 1.36722E-03 1.00000E+10 1.31867E-03 0.0000000000000000 + -1000000002 4.51179E-01 5.49913E-01 7.17197E-01 7.69389E-01 1.03896E+00 1.11635E+00 1.58770E+00 1.76931E+00 0.00000E+00 0.0000000000000000 + -1000000003 3.92154E+00 4.51179E-01 1.76931E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.0000000000000000 + -1000000004 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 1.43490E-01 1.02277E-01 0.00000E+00 8.74592E-02 0.0000000000000000 + -1000000005 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 2.70519E-03 6.68392E-03 1.00000E+10 7.53879E-03 0.0000000000000000 + -1000000006 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 1.00000E+00 0.00000E+00 0.0000000000000000 + -1000000007 0.00000E+00 3.70000E+01 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.0000000000000000 + -1000000008 3.86702E-02 4.70410E-03 -5.81470E-04 5.38516E-02 3.02526E-02 -7.78857E-01 -3.12890E-01 0.00000E+00 -6.59977E-01 0.0000000000000000 diff --git a/vignette/models/drugx-oral-1cmt-101/mod1.lst b/vignette/models/drugx-oral-1cmt-101/mod1.lst new file mode 100644 index 0000000..b5b35c6 --- /dev/null +++ b/vignette/models/drugx-oral-1cmt-101/mod1.lst @@ -0,0 +1,671 @@ +Tue 04/09/2024 +03:11 PM +$PROBLEM ev_no-delay_first-order_one-compartment_linear +$INPUT ID TIME EVID AMT DV RACEN WTKG Race=DROP +$DATA F1003-Asian-PK-Study.csv IGNORE=@ +$SUBROUTINE ADVAN13 TRANS1 TOL=9 SUBROUTINES=D +$MODEL COMP=(DEPOT,DEFDOSE) COMP=(CENTRAL,DEFOBS) +$PK + +TVKA = THETA(1) +KA = TVKA + +TVCL = THETA(2)*(WTKG/71.0)**THETA(4) +CL = TVCL*EXP(ETA(1)) + +TVV = THETA(3)*(WTKG/71.0)**THETA(5) +V = TVV*EXP(ETA(2)) +S2 = V + +$DES + +DADT(1) = -KA*A(1) +DADT(2) = KA*A(1) - (CL/V)*A(2) + +$ERROR + +IPRED = F +IRES = DV-IPRED +W = SQRT(IPRED**2*SIGMA(1,1)) +IWRES = IRES/W +Y = F + F*EPS(1) + +$THETA (0,0.783) ; KA; 1/hr ;Absorption Rate Constant + (0,17.3) ; CL; L/hr ;Clearance + (0,84.0) ; V; L ;Volume of Distribution + 1.83 ; WTonCL + 1 ; WTonV +$OMEGA BLOCK(2) + 0.0103 ; CL_ + 0.00 0.111 ; V_ +$SIGMA 0.0206 ; Proportional +$ESTIMATION METHOD=1 INTER NOABORT MAXEVAL=9999 PRINT=5 NSIG=3 SIGL=9 + NOTHETABOUNDTEST NOOMEGABOUNDTEST NOSIGMABOUNDTEST +$COVARIANCE PRINT=E UNCONDITIONAL +$TABLE ID TIME DV MDV EVID IPRED CWRES IWRES ONEHEADER NOPRINT + FILE=sdtab1 +$TABLE ID KA CL V ETAS(1:LAST) ONEHEADER NOPRINT FILE=patab1 ; model parameters +$TABLE ID RACEN ONEHEADER NOPRINT FILE=catab1 ; categorical covariates +$TABLE ID WTKG ONEHEADER NOPRINT FILE=cotab1 ; continuous covariates + + +NM-TRAN MESSAGES + + WARNINGS AND ERRORS (IF ANY) FOR PROBLEM 1 + + (WARNING 2) NM-TRAN INFERS THAT THE DATA ARE POPULATION. + + (WARNING 79) SIGMA IS USED ON THE RIGHT. WITH A SUBSEQUENT RUN, IF AN + INITIAL ESTIMATE OF A DIAGONAL BLOCK OF SIGMA IS TO BE COMPUTED BY + NONMEM, THAT BLOCK WILL BE SET TO AN IDENTITY MATRIX DURING THAT + COMPUTATION. THIS COULD LEAD TO AN ARITHMETIC EXCEPTION.* + + * THE MAXIMUM NUMBER OF WARNINGS OF ONE OR MORE TYPES WAS REACHED. + IT IS POSSIBLE THAT SOME WARNING MESSAGES WERE SUPPRESSED. + +License Registered to: Enhanced Pharmacodynamics LLC +Expiration Date: 14 SEP 2024 +Current Date: 9 APR 2024 +Days until program expires : 155 +1NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM) VERSION 7.4.4 + ORIGINALLY DEVELOPED BY STUART BEAL, LEWIS SHEINER, AND ALISON BOECKMANN + CURRENT DEVELOPERS ARE ROBERT BAUER, ICON DEVELOPMENT SOLUTIONS, + AND ALISON BOECKMANN. IMPLEMENTATION, EFFICIENCY, AND STANDARDIZATION + PERFORMED BY NOUS INFOSYSTEMS. + + PROBLEM NO.: 1 + ev_no-delay_first-order_one-compartment_linear +0DATA CHECKOUT RUN: NO + DATA SET LOCATED ON UNIT NO.: 2 + THIS UNIT TO BE REWOUND: NO + NO. OF DATA RECS IN DATA SET: 1500 + NO. OF DATA ITEMS IN DATA SET: 8 + ID DATA ITEM IS DATA ITEM NO.: 1 + DEP VARIABLE IS DATA ITEM NO.: 5 + MDV DATA ITEM IS DATA ITEM NO.: 8 +0INDICES PASSED TO SUBROUTINE PRED: + 3 2 4 0 0 0 0 0 0 0 0 +0LABELS FOR DATA ITEMS: + ID TIME EVID AMT DV RACEN WTKG MDV +0(NONBLANK) LABELS FOR PRED-DEFINED ITEMS: + KA CL V IPRED IWRES +0FORMAT FOR DATA: + (E4.0,E5.0,E2.0,E4.0,E12.0,E2.0,E7.0,1F2.0) + + TOT. NO. OF OBS RECS: 1400 + TOT. NO. OF INDIVIDUALS: 100 +0LENGTH OF THETA: 5 +0DEFAULT THETA BOUNDARY TEST OMITTED: YES +0OMEGA HAS BLOCK FORM: + 1 + 1 1 +0DEFAULT OMEGA BOUNDARY TEST OMITTED: YES +0SIGMA HAS SIMPLE DIAGONAL FORM WITH DIMENSION: 1 +0DEFAULT SIGMA BOUNDARY TEST OMITTED: YES +0INITIAL ESTIMATE OF THETA: + LOWER BOUND INITIAL EST UPPER BOUND + 0.0000E+00 0.7830E+00 0.1000E+07 + 0.0000E+00 0.1730E+02 0.1000E+07 + 0.0000E+00 0.8400E+02 0.1000E+07 + -0.1000E+07 0.1830E+01 0.1000E+07 + -0.1000E+07 0.1000E+01 0.1000E+07 +0INITIAL ESTIMATE OF OMEGA: + BLOCK SET NO. BLOCK FIXED + 1 NO + 0.1030E-01 + 0.0000E+00 0.1110E+00 +0INITIAL ESTIMATE OF SIGMA: + 0.2060E-01 +0COVARIANCE STEP OMITTED: NO + EIGENVLS. PRINTED: YES + SPECIAL COMPUTATION: NO + COMPRESSED FORMAT: NO + GRADIENT METHOD USED: NOSLOW + SIGDIGITS ETAHAT (SIGLO): -1 + SIGDIGITS GRADIENTS (SIGL): -1 + EXCLUDE COV FOR FOCE (NOFCOV): NO + TURN OFF Cholesky Transposition of R Matrix (CHOLROFF): NO + KNUTHSUMOFF: -1 + RESUME COV ANALYSIS (RESUME): NO + SIR SAMPLE SIZE (SIRSAMPLE): -1 + NON-LINEARLY TRANSFORM THETAS DURING COV (THBND): 1 + PRECONDTIONING CYCLES (PRECOND): 0 + PRECONDTIONING TYPES (PRECONDS): TOS + FORCED PRECONDTIONING CYCLES (PFCOND):0 + PRECONDTIONING TYPE (PRETYPE): 0 + FORCED POS. DEFINITE SETTING: (FPOSDEF):0 +0TABLES STEP OMITTED: NO + NO. OF TABLES: 4 + SEED NUMBER (SEED): 11456 + RANMETHOD: 3U + MC SAMPLES (ESAMPLE): 300 + WRES SQUARE ROOT TYPE (WRESCHOL): EIGENVALUE +0-- TABLE 1 -- +0RECORDS ONLY: ALL +04 COLUMNS APPENDED: YES + PRINTED: NO + HEADERS: ONE + FILE TO BE FORWARDED: NO + FORMAT: S1PE11.4 + LFORMAT: + RFORMAT: + FIXED_EFFECT_ETAS: +0USER-CHOSEN ITEMS: + ID TIME DV MDV EVID IPRED CWRES IWRES +0-- TABLE 2 -- +0RECORDS ONLY: ALL +04 COLUMNS APPENDED: YES + PRINTED: NO + HEADERS: ONE + FILE TO BE FORWARDED: NO + FORMAT: S1PE11.4 + LFORMAT: + RFORMAT: + FIXED_EFFECT_ETAS: +0USER-CHOSEN ITEMS: + ID KA CL V ETA1 ETA2 +0-- TABLE 3 -- +0RECORDS ONLY: ALL +04 COLUMNS APPENDED: YES + PRINTED: NO + HEADERS: ONE + FILE TO BE FORWARDED: NO + FORMAT: S1PE11.4 + LFORMAT: + RFORMAT: + FIXED_EFFECT_ETAS: +0USER-CHOSEN ITEMS: + ID RACEN +0-- TABLE 4 -- +0RECORDS ONLY: ALL +04 COLUMNS APPENDED: YES + PRINTED: NO + HEADERS: ONE + FILE TO BE FORWARDED: NO + FORMAT: S1PE11.4 + LFORMAT: + RFORMAT: + FIXED_EFFECT_ETAS: +0USER-CHOSEN ITEMS: + ID WTKG +1DOUBLE PRECISION PREDPP VERSION 7.4.4 + + GENERAL NONLINEAR KINETICS MODEL WITH STIFF/NONSTIFF EQUATIONS (LSODA, ADVAN13) +0MODEL SUBROUTINE USER-SUPPLIED - ID NO. 9999 +0MAXIMUM NO. OF BASIC PK PARAMETERS: 3 +0COMPARTMENT ATTRIBUTES + COMPT. NO. FUNCTION INITIAL ON/OFF DOSE DEFAULT DEFAULT + STATUS ALLOWED ALLOWED FOR DOSE FOR OBS. + 1 DEPOT ON YES YES YES NO + 2 CENTRAL ON YES YES NO YES + 3 OUTPUT OFF YES NO NO NO + INITIAL (BASE) TOLERANCE SETTINGS: + NRD (RELATIVE) VALUE(S) OF TOLERANCE: 9 + ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE: 12 +1 + ADDITIONAL PK PARAMETERS - ASSIGNMENT OF ROWS IN GG + COMPT. NO. INDICES + SCALE BIOAVAIL. ZERO-ORDER ZERO-ORDER ABSORB + FRACTION RATE DURATION LAG + 1 * * * * * + 2 4 * * * * + 3 * - - - - + - PARAMETER IS NOT ALLOWED FOR THIS MODEL + * PARAMETER IS NOT SUPPLIED BY PK SUBROUTINE; + WILL DEFAULT TO ONE IF APPLICABLE +0DATA ITEM INDICES USED BY PRED ARE: + EVENT ID DATA ITEM IS DATA ITEM NO.: 3 + TIME DATA ITEM IS DATA ITEM NO.: 2 + DOSE AMOUNT DATA ITEM IS DATA ITEM NO.: 4 + +0PK SUBROUTINE CALLED WITH EVERY EVENT RECORD. + PK SUBROUTINE NOT CALLED AT NONEVENT (ADDITIONAL OR LAGGED) DOSE TIMES. +0ERROR SUBROUTINE CALLED WITH EVERY EVENT RECORD. +0DES SUBROUTINE USES COMPACT STORAGE MODE. +1 + + + #TBLN: 1 + #METH: First Order Conditional Estimation with Interaction + + ESTIMATION STEP OMITTED: NO + ANALYSIS TYPE: POPULATION + NUMBER OF SADDLE POINT RESET ITERATIONS: 0 + GRADIENT METHOD USED: NOSLOW + CONDITIONAL ESTIMATES USED: YES + CENTERED ETA: NO + EPS-ETA INTERACTION: YES + LAPLACIAN OBJ. FUNC.: NO + NO. OF FUNCT. EVALS. ALLOWED: 9999 + NO. OF SIG. FIGURES REQUIRED: 3 + INTERMEDIATE PRINTOUT: YES + ESTIMATE OUTPUT TO MSF: NO + ABORT WITH PRED EXIT CODE 1: NO + IND. OBJ. FUNC. VALUES SORTED: NO + NUMERICAL DERIVATIVE + FILE REQUEST (NUMDER): NONE + MAP (ETAHAT) ESTIMATION METHOD (OPTMAP): 0 + ETA HESSIAN EVALUATION METHOD (ETADER): 0 + INITIAL ETA FOR MAP ESTIMATION (MCETA): 0 + SIGDIGITS FOR MAP ESTIMATION (SIGLO): 9 + GRADIENT SIGDIGITS OF + FIXED EFFECTS PARAMETERS (SIGL): 9 + NOPRIOR SETTING (NOPRIOR): OFF + NOCOV SETTING (NOCOV): OFF + DERCONT SETTING (DERCONT): OFF + FINAL ETA RE-EVALUATION (FNLETA): ON + EXCLUDE NON-INFLUENTIAL (NON-INFL.) ETAS + IN SHRINKAGE (ETASTYPE): NO + NON-INFL. ETA CORRECTION (NONINFETA): OFF + RAW OUTPUT FILE (FILE): psn.ext + EXCLUDE TITLE (NOTITLE): NO + EXCLUDE COLUMN LABELS (NOLABEL): NO + FORMAT FOR ADDITIONAL FILES (FORMAT): S1PE12.5 + PARAMETER ORDER FOR OUTPUTS (ORDER): TSOL + WISHART PRIOR DF INTERPRETATION (WISHTYPE):0 + KNUTHSUMOFF: 0 + INCLUDE LNTWOPI: NO + INCLUDE CONSTANT TERM TO PRIOR (PRIORC): NO + INCLUDE CONSTANT TERM TO OMEGA (ETA) (OLNTWOPI):NO + ADDITIONAL CONVERGENCE TEST (CTYPE=4)?: NO + EM OR BAYESIAN METHOD USED: NONE + + TOLERANCES FOR ESTIMATION/EVALUATION STEP: + NRD (RELATIVE) VALUE(S) OF TOLERANCE: 9 + ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE: 12 + TOLERANCES FOR COVARIANCE STEP: + NRD (RELATIVE) VALUE(S) OF TOLERANCE: 9 + ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE: 12 + TOLERANCES FOR TABLE/SCATTER STEP: + NRD (RELATIVE) VALUE(S) OF TOLERANCE: 9 + ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE: 12 + + THE FOLLOWING LABELS ARE EQUIVALENT + PRED=PREDI + RES=RESI + WRES=WRESI + IWRS=IWRESI + IPRD=IPREDI + IRS=IRESI + + MONITORING OF SEARCH: + + +0ITERATION NO.: 0 OBJECTIVE VALUE: -6481.61695802832 NO. OF FUNC. EVALS.: 8 + CUMULATIVE NO. OF FUNC. EVALS.: 8 + NPARAMETR: 7.8300E-01 1.7300E+01 8.4000E+01 1.8300E+00 1.0000E+00 1.0300E-02 1.1100E-01 2.0600E-02 + PARAMETER: 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 + GRADIENT: 1.0023E+01 -2.5296E+01 -2.4393E+01 -1.6530E+02 -4.1748E+02 -4.7420E-01 1.5420E+02 2.7740E+00 + +0ITERATION NO.: 5 OBJECTIVE VALUE: -6548.92493583334 NO. OF FUNC. EVALS.: 48 + CUMULATIVE NO. OF FUNC. EVALS.: 56 + NPARAMETR: 8.2425E-01 1.7375E+01 8.9644E+01 1.9419E+00 2.1075E+00 1.0406E-02 1.6033E-02 2.0643E-02 + PARAMETER: 1.5134E-01 1.0432E-01 1.6502E-01 1.0611E-01 2.1075E-01 1.0512E-01 -8.6745E-01 1.0103E-01 + GRADIENT: 6.2602E+02 -1.6029E+02 1.5773E+02 5.8002E+02 2.2952E+03 -1.8179E+00 -2.6739E+01 -3.8335E+01 + +0ITERATION NO.: 10 OBJECTIVE VALUE: -6639.52360317143 NO. OF FUNC. EVALS.: 49 + CUMULATIVE NO. OF FUNC. EVALS.: 105 + NPARAMETR: 7.9254E-01 1.7345E+01 8.5272E+01 1.9097E+00 1.5673E+00 8.7425E-03 6.8631E-03 2.0454E-02 + PARAMETER: 1.1211E-01 1.0262E-01 1.1503E-01 1.0435E-01 1.5673E-01 1.8027E-02 -1.2917E+00 9.6442E-02 + GRADIENT: 2.7685E+02 -7.5585E+00 -2.3922E+02 9.4589E+02 -1.7651E+02 -3.3635E+01 -1.5951E+01 -1.5793E+01 + +0ITERATION NO.: 15 OBJECTIVE VALUE: -6645.44690748923 NO. OF FUNC. EVALS.: 46 + CUMULATIVE NO. OF FUNC. EVALS.: 151 + NPARAMETR: 7.8239E-01 1.7338E+01 8.5824E+01 1.8505E+00 1.5807E+00 1.0456E-02 7.6576E-03 2.0590E-02 + PARAMETER: 9.9217E-02 1.0217E-01 1.2149E-01 1.0112E-01 1.5807E-01 1.0750E-01 -1.2369E+00 9.9767E-02 + GRADIENT: -1.8742E-01 3.7008E-01 -7.7906E-03 1.5392E+00 4.0582E-01 -5.2822E-02 1.5006E-01 2.4771E-01 + +0ITERATION NO.: 20 OBJECTIVE VALUE: -6645.44730274261 NO. OF FUNC. EVALS.: 73 + CUMULATIVE NO. OF FUNC. EVALS.: 224 + NPARAMETR: 7.8242E-01 1.7338E+01 8.5830E+01 1.8512E+00 1.5811E+00 1.0461E-02 7.6491E-03 2.0589E-02 + PARAMETER: 9.9260E-02 1.0221E-01 1.2155E-01 1.0116E-01 1.5811E-01 1.0773E-01 -1.2375E+00 9.9744E-02 + GRADIENT: -6.2908E-02 -1.5248E-01 9.3741E-02 -2.0940E+00 -5.9376E-01 1.3092E-02 2.0193E-02 6.4205E-02 + + #TERM: +0MINIMIZATION SUCCESSFUL + NO. OF FUNCTION EVALUATIONS USED: 224 + NO. OF SIG. DIGITS IN FINAL EST.: 3.5 + + ETABAR IS THE ARITHMETIC MEAN OF THE ETA-ESTIMATES, + AND THE P-VALUE IS GIVEN FOR THE NULL HYPOTHESIS THAT THE TRUE MEAN IS 0. + + ETABAR: -4.1940E-05 -6.8459E-04 + SE: 9.6771E-03 7.6213E-03 + N: 100 100 + + P VAL.: 9.9654E-01 9.2843E-01 + + ETASHRINKSD(%) 4.9065E+00 1.2420E+01 + ETASHRINKVR(%) 9.5723E+00 2.3297E+01 + EBVSHRINKSD(%) 5.3297E+00 1.2753E+01 + EBVSHRINKVR(%) 1.0375E+01 2.3879E+01 + EPSSHRINKSD(%) 5.8347E+00 + EPSSHRINKVR(%) 1.1329E+01 + + + TOTAL DATA POINTS NORMALLY DISTRIBUTED (N): 1400 + N*LOG(2PI) CONSTANT TO OBJECTIVE FUNCTION: 2573.0278929730835 + OBJECTIVE FUNCTION VALUE WITHOUT CONSTANT: -6645.4473027426147 + OBJECTIVE FUNCTION VALUE WITH CONSTANT: -4072.4194097695313 + REPORTED OBJECTIVE FUNCTION DOES NOT CONTAIN CONSTANT + + TOTAL EFFECTIVE ETAS (NIND*NETA): 200 + + #TERE: + Elapsed estimation time in seconds: 49.94 + Elapsed covariance time in seconds: 57.79 + Elapsed postprocess time in seconds: 0.86 +1 + + + + + + + + + + + + + + + + + + + + + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + #OBJT:************** MINIMUM VALUE OF OBJECTIVE FUNCTION ******************** + ******************** ******************** + ************************************************************************************************************************ + + + + + + + #OBJV:******************************************** -6645.447 ************************************************** +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** FINAL PARAMETER ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + + THETA - VECTOR OF FIXED EFFECTS PARAMETERS ********* + + + TH 1 TH 2 TH 3 TH 4 TH 5 + + 7.82E-01 1.73E+01 8.58E+01 1.85E+00 1.58E+00 + + + + OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ******** + + + ETA1 ETA2 + + ETA1 ++ 1.05E-02 + + ETA2 ++ 0.00E+00 7.65E-03 + + + + SIGMA - COV MATRIX FOR RANDOM EFFECTS - EPSILONS **** + + + EPS1 + + EPS1 ++ 2.06E-02 + +1 + + + OMEGA - CORR MATRIX FOR RANDOM EFFECTS - ETAS ******* + + + ETA1 ETA2 + + ETA1 ++ 1.02E-01 + + ETA2 ++ 0.00E+00 8.75E-02 + + + + SIGMA - CORR MATRIX FOR RANDOM EFFECTS - EPSILONS *** + + + EPS1 + + EPS1 ++ 1.43E-01 + +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** STANDARD ERROR OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + + THETA - VECTOR OF FIXED EFFECTS PARAMETERS ********* + + + TH 1 TH 2 TH 3 TH 4 TH 5 + + 9.56E-03 1.93E-01 9.54E-01 5.61E-02 5.84E-02 + + + + OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ******** + + + ETA1 ETA2 + + ETA1 ++ 1.37E-03 + + ETA2 ++ ......... 1.32E-03 + + + + SIGMA - COV MATRIX FOR RANDOM EFFECTS - EPSILONS **** + + + EPS1 + + EPS1 ++ 7.76E-04 + +1 + + + OMEGA - CORR MATRIX FOR RANDOM EFFECTS - ETAS ******* + + + ETA1 ETA2 + + ETA1 ++ 6.68E-03 + + ETA2 ++ ......... 7.54E-03 + + + + SIGMA - CORR MATRIX FOR RANDOM EFFECTS - EPSILONS *** + + + EPS1 + + EPS1 ++ 2.71E-03 + +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** COVARIANCE MATRIX OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + TH 1 TH 2 TH 3 TH 4 TH 5 OM11 OM12 OM22 SG11 + + TH 1 ++ 9.14E-05 + + TH 2 ++ 4.43E-04 3.74E-02 + + TH 3 ++ 3.98E-03 4.32E-02 9.11E-01 + + TH 4 ++ 2.63E-05 -1.29E-03 2.97E-03 3.15E-03 + + TH 5 ++ -3.42E-05 1.99E-04 -9.29E-03 -6.97E-04 3.41E-03 + + OM11 ++ 1.65E-06 4.01E-05 -1.69E-05 1.74E-07 2.57E-06 1.87E-06 + + OM12 ++ ......... ......... ......... ......... ......... ......... ......... + + OM22 ++ 1.61E-06 3.00E-05 -1.13E-05 -1.14E-05 1.72E-05 5.97E-07 ......... 1.74E-06 + + SG11 ++ 3.04E-07 2.42E-05 1.35E-04 -6.69E-07 -3.62E-06 1.49E-07 ......... -2.40E-07 6.03E-07 + +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** CORRELATION MATRIX OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + TH 1 TH 2 TH 3 TH 4 TH 5 OM11 OM12 OM22 SG11 + + TH 1 ++ 9.56E-03 + + TH 2 ++ 2.40E-01 1.93E-01 + + TH 3 ++ 4.36E-01 2.34E-01 9.54E-01 + + TH 4 ++ 4.90E-02 -1.19E-01 5.54E-02 5.61E-02 + + TH 5 ++ -6.12E-02 1.76E-02 -1.67E-01 -2.13E-01 5.84E-02 + + OM11 ++ 1.26E-01 1.52E-01 -1.30E-02 2.27E-03 3.22E-02 1.37E-03 + + OM12 ++ ......... ......... ......... ......... ......... ......... ......... + + OM22 ++ 1.28E-01 1.18E-01 -8.99E-03 -1.54E-01 2.23E-01 3.31E-01 ......... 1.32E-03 + + SG11 ++ 4.09E-02 1.61E-01 1.82E-01 -1.54E-02 -7.98E-02 1.40E-01 ......... -2.34E-01 7.76E-04 + +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** INVERSE COVARIANCE MATRIX OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + TH 1 TH 2 TH 3 TH 4 TH 5 OM11 OM12 OM22 SG11 + + TH 1 ++ 1.43E+04 + + TH 2 ++ -9.46E+01 3.08E+01 + + TH 3 ++ -5.89E+01 -9.68E-01 1.48E+00 + + TH 4 ++ -1.27E+02 1.24E+01 -8.02E-01 3.46E+02 + + TH 5 ++ 2.23E+01 -1.82E+00 3.12E+00 5.79E+01 3.28E+02 + + OM11 ++ -8.99E+03 -3.90E+02 1.16E+02 -1.10E+03 5.49E+02 6.56E+05 + + OM12 ++ ......... ......... ......... ......... ......... ......... ......... + + OM22 ++ -8.80E+03 -3.57E+02 -3.44E+01 2.20E+03 -3.02E+03 -2.59E+05 ......... 7.75E+05 + + SG11 ++ 8.46E+03 -1.01E+03 -2.87E+02 1.62E+03 6.69E+01 -2.68E+05 ......... 3.83E+05 1.98E+06 + +1 + + + + + + + + + + + + + + + + + + + + + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** EIGENVALUES OF COR MATRIX OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + 1 2 3 4 5 6 7 8 + + 4.51E-01 5.50E-01 7.17E-01 7.69E-01 1.04E+00 1.12E+00 1.59E+00 1.77E+00 + + Elapsed finaloutput time in seconds: 0.90 + #CPUT: Total CPU Time in Seconds, 108.422 +Stop Time: +Tue 04/09/2024 +03:13 PM diff --git a/vignette/models/drugx-oral-1cmt-101/mrgsolve_code_drugx-oral.R b/vignette/models/drugx-oral-1cmt-101/mrgsolve_code_drugx-oral.R new file mode 100644 index 0000000..7d03ff5 --- /dev/null +++ b/vignette/models/drugx-oral-1cmt-101/mrgsolve_code_drugx-oral.R @@ -0,0 +1,52 @@ +code <- ' +$PROB ev_no-delay_first-order_one-compartment_linear + +$PARAM + +WTKG=NA_real_ + +$THETA + +0.782 17.3 85.8 1.85 1.58 + +$CMT + +DEPOT +CENTRAL + +$MAIN + +/* NOTE: There is no guarantee to the accuracy of the NONMEM to mrgsolve translator. It remains the responsibility of the user to validate the resulting mrgsolve code. */ + +/* NOTE: The nonmem2mrgsolve package remains in active development, please report bugs and feature requests to improve future versions. */ +/* NOTE: If you find nonmem2mrgsolve helpful, please consider giving it a star at github.com/Andy00000000000/nonmem2mrgsolve. */ + +/* NOTE: The translator does not currently convert T or TIME to SOLVERTIME. */ +/* NOTE: The translator does not currently convert MTIME() to self.mtime(). */ + +double TVKA = THETA1; +double KA = TVKA; +double TVCL = THETA2*pow((WTKG/71.0),THETA4); +double CL = TVCL*exp(ETA(1)); +double TVV = THETA3*pow((WTKG/71.0),THETA5); +double V = TVV*exp(ETA(2)); +double S2 = V; + +$ODE + +dxdt_DEPOT=-KA*DEPOT; +dxdt_CENTRAL=KA*DEPOT - (CL/V)*CENTRAL; + +$OMEGA @block + +0.0105 +0 0.00765 + +$CAPTURE + +KA +CL +V +WTKG + +' \ No newline at end of file diff --git a/vignette/models/drugx-oral-1cmt-101/run_nonmem2mrgsolve_drugx.R b/vignette/models/drugx-oral-1cmt-101/run_nonmem2mrgsolve_drugx.R new file mode 100644 index 0000000..6577367 --- /dev/null +++ b/vignette/models/drugx-oral-1cmt-101/run_nonmem2mrgsolve_drugx.R @@ -0,0 +1,22 @@ +## Start #### + +# devtools::install_github("Andy00000000000/nonmem2mrgsolve") +# setwd("...") + +library("nonmem2mrgsolve") + +nonmem2mrgsolve( + "mod1.ctl", # filename + "./vignette/models/drugx-oral-1cmt-101/", # dir + out.filename = "mrgsolve_code_drugx-oral", + sigdig = 3 +) + +source("./vignette/models/drugx-oral-1cmt-101/mrgsolve_code_drugx-oral.R") +mrgsolve::mcode("Test_Unmodified_Translation",code) + +# Shortcomings of the current translation which requires the user's attention: +# +# None, this model translates exactly as needed + +## End #### diff --git a/vignette/models/evolocumab-tmdd-qss-pkpd-101/mod1.ctl b/vignette/models/evolocumab-tmdd-qss-pkpd-101/mod1.ctl new file mode 100644 index 0000000..dfa732a --- /dev/null +++ b/vignette/models/evolocumab-tmdd-qss-pkpd-101/mod1.ctl @@ -0,0 +1,198 @@ +$PROB Simultaneous PKPD of the human anti-PCSK9 mAb evolocumab + +$ABBR PROTECT + +$INPUT ID TIME DV AMT ADDL II CMT MDV EVID DOSEMG HEALTHY + +$DATA "../../data/NM_data_evoPKPD.csv" IGNORE=@ + +$SUBROUTINES ADVAN13 TRANS1 TOL=6 + +$MODEL +COMP = (DEPOT, DEFDOSE) ; evolocumab SC depot +COMP = (TDA) ; total evolocumab amount in central +COMP = (TLC, NODOSE) ; total ligand (PCSK9) concentration in central +COMP = (CLDL, NODOSE) ; LDL cholesterol concentration + +$PK + +CALLFL=-2 + +;;;;; TMDD PK ;;;;; + +TVKA = THETA(1) +KA = TVKA*EXP(ETA(1)) + +TVV = THETA(2) +V = TVV*EXP(ETA(2)) + +TVCL = THETA(3) +CL = TVCL*EXP(ETA(3)) + +TVKDEG = THETA(4) +KDEG = TVKDEG*EXP(ETA(4)) + +TVPCSK9_0 = THETA(5)*THETA(8)**(HEALTHY) +PCSK9_0 = TVPCSK9_0*EXP(ETA(5)) + +TVKSS = THETA(6) +KSS = TVKSS*EXP(ETA(6)) + +TVKINT = THETA(7) +KINT = TVKINT*EXP(ETA(7)) + +KEL = CL/V + +KSYN = KDEG*PCSK9_0 ; zero-order PCSK9 production rate (nM/day) + +F1 = THETA(9) + +A_0(3) = PCSK9_0 ; change initial condition from default of zero + +;;;;; PD ;;;;; + +TVKOUT = THETA(10) +KOUT = TVKOUT*EXP(ETA(8)) + +TVLDLC_0 = THETA(11) +LDLC_0 = TVLDLC_0*EXP(ETA(9)) + +TVIMAX = THETA(12) +IMAX = TVIMAX*EXP(ETA(10)) + +TVIC50 = THETA(13) +IC50 = TVIC50*EXP(ETA(11)) + +INH0 = (IMAX*PCSK9_0)/(IC50+PCSK9_0) + +KIN = KOUT*(1.0-INH0)*LDLC_0 ; zero-order LDL-C production rate (mg/dL/day) + +A_0(4) = LDLC_0 ; change initial condition from default of zero + +$DES + +;;;;; TMDD PK ;;;;; + +TDC = A(2)/V ; total evolocumab concentration (nM) +FDC = 0.5*((TDC-A(3)-KSS) + SQRT((TDC-A(3)-KSS)**2.0 + 4.0*KSS*TDC)) ; free evolocumab concentration (nM) +FLC = A(3) - (TDC - FDC) ; free PCSK9 concentration (nM) + +DADT(1) = -KA*A(1) ; evolocumab SC depot (nmol) +DADT(2) = KA*A(1) - KEL*FDC*V - (KINT*A(3)*FDC*V)/(KSS+FDC) ; total evolocumab amount in central (nmol) +DADT(3) = KSYN - KDEG*A(3) - ((KINT-KDEG)*FDC*A(3))/(KSS+FDC) ; total PCSK9 concentration in central (nM) + +;;;;; PD ;;;;; + +INH = (IMAX*PCSK9_0)/(IC50+PCSK9_0) +IF (TIME.GT.0) INH = (IMAX*FLC)/(IC50+FLC) + +DADT(4) = KIN - KOUT*(1.0-INH)*A(4) ; LDL-C concentration (mg/dL) + +$ERROR + +TDC2 = A(2)/V ; total evolocumab concentration (nM) +FDC2 = 0.5*((TDC2-A(3)-KSS) + SQRT((TDC2-A(3)-KSS)**2.0 + 4.0*KSS*TDC2)) ; free evolocumab concentration (nM) +FLC2 = A(3) - (TDC2 - FDC2) ; free PCSK9 concentration (nM) + +DRUG=0 +IF(CMT.EQ.2)DRUG=1 + +LIG=0 +IF(CMT.EQ.3)LIG=1 + +LDL=0 +IF(CMT.EQ.4)LDL=1 + +IF(CMT.EQ.2)THEN + IPRED = FDC2*144/1000 ; convert nM to mcg/mL, approximate MW of evolocumab is 144 kDa + IRES = DV-IPRED + W = SQRT(IPRED**2*SIGMA(1,1)+SIGMA(2,2)) + IWRES = IRES/W +ENDIF + +IF(CMT.EQ.3)THEN + IPRED = FLC2 + IRES = DV-IPRED + W = SQRT(IPRED**2*SIGMA(3,3)+SIGMA(4,4)) + IWRES = IRES/W +ENDIF + +IF(CMT.EQ.4)THEN + IPRED = F + IRES = DV-IPRED + W = SQRT(IPRED**2*SIGMA(5,5)+SIGMA(6,6)) + IWRES = IRES/W +ENDIF + +Y1 = IPRED + IPRED*EPS(1) + EPS(2) +Y2 = IPRED + IPRED*EPS(3) + EPS(4) +Y3 = IPRED + IPRED*EPS(5) + EPS(6) + +Y = Y1*DRUG + Y2*LIG + Y3*LDL + +$THETA +0.2; KA; 1/day ; first-order evolocumab absorption rate constant +3; V; L ; evolocumab volume of distribution +0.3; CL; L/day ; evolocumab clearance +2; KDEG; 1/day ; first-order PCSK9 degradation rate constant +5; PCSK9_0; nM ; initial PCSK9 concentration +0.3; KSS; nM ; steady-state constant +0.05; KINT; 1/day ; first-order evolocumab-PCSK9 complex elimination rate constant +0.6; PCSK9_0_HEALTHY; none ; fold change in initial PCSK9 conc. for healthy vs. statin-treated +0.72 FIXED; F1; none ; evolocumab SC bioavailability +0.3; KOUT; 1/day ; first-order elimination rate constant for LDL-C +100; LDLC_0; mg/dL ; baseline LDL-C concentration +1 FIXED; IMAX; none ; maximal inhibition +1; IC50; nM ; serum unbound PCSK9 concentration associated with half-maximal inhibition + +$OMEGA BLOCK(1) +0.1; KA + +$OMEGA BLOCK(1) +0.03; V + +$OMEGA BLOCK(1) +0.1; CL + +$OMEGA BLOCK(1) +0 FIXED; KDEG + +$OMEGA BLOCK(1) +0.03; PCSK9_0 + +$OMEGA BLOCK(1) +0.1; KSS + +$OMEGA BLOCK(1) +0 FIXED; KINT + +$OMEGA BLOCK(1) +0 FIXED; KOUT + +$OMEGA BLOCK(1) +0.04; LDLC_0 + +$OMEGA BLOCK(1) +0 FIXED; IMAX + +$OMEGA BLOCK(1) +0.1; IC50 + +$SIGMA +0.01 ; Evolocumab_Prop +0 FIXED ; Evolocumab_Add +0.01 ; PCSK9_Prop +0 FIXED ; PCSK9_Add +0.01 ; LDLC_Prop +20 ; LDLC_Add + +$ESTIMATION METHOD=1 INTER NOHABORT MAXEVAL=9999 PRINT=5 NSIG=1 SIGL=3 + +$COVARIANCE PRINT=E MATRIX=S UNCONDITIONAL + +;*...............80 Character limit............................................* +$TABLE ID TIME DV CMT MDV EVID IPRED CWRES IWRES ONEHEADER NOPRINT FILE=sdtab1 +$TABLE ID KA V CL KDEG PCSK9_0 KSS KINT KOUT LDLC_0 IMAX IC50 ONEHEADER + NOPRINT FILE=patab1 ; model parameters +$TABLE ID DOSEMG HEALTHY ONEHEADER NOPRINT FILE=catab1 ; categorical covariates +$TABLE ID ONEHEADER NOPRINT FILE=cotab1 ; continuous covariates \ No newline at end of file diff --git a/vignette/models/evolocumab-tmdd-qss-pkpd-101/mod1.ext b/vignette/models/evolocumab-tmdd-qss-pkpd-101/mod1.ext new file mode 100644 index 0000000..1ada9d9 --- /dev/null +++ b/vignette/models/evolocumab-tmdd-qss-pkpd-101/mod1.ext @@ -0,0 +1,15 @@ +TABLE NO. 1: First Order Conditional Estimation with Interaction: Goal Function=MINIMUM VALUE OF OBJECTIVE FUNCTION: Problem=1 Subproblem=0 Superproblem1=0 Iteration1=0 Superproblem2=0 Iteration2=0 + ITERATION THETA1 THETA2 THETA3 THETA4 THETA5 THETA6 THETA7 THETA8 THETA9 THETA10 THETA11 THETA12 THETA13 SIGMA(1,1) SIGMA(2,1) SIGMA(2,2) SIGMA(3,1) SIGMA(3,2) SIGMA(3,3) SIGMA(4,1) SIGMA(4,2) SIGMA(4,3) SIGMA(4,4) SIGMA(5,1) SIGMA(5,2) SIGMA(5,3) SIGMA(5,4) SIGMA(5,5) SIGMA(6,1) SIGMA(6,2) SIGMA(6,3) SIGMA(6,4) SIGMA(6,5) SIGMA(6,6) OMEGA(1,1) OMEGA(2,1) OMEGA(2,2) OMEGA(3,1) OMEGA(3,2) OMEGA(3,3) OMEGA(4,1) OMEGA(4,2) OMEGA(4,3) OMEGA(4,4) OMEGA(5,1) OMEGA(5,2) OMEGA(5,3) OMEGA(5,4) OMEGA(5,5) OMEGA(6,1) OMEGA(6,2) OMEGA(6,3) OMEGA(6,4) OMEGA(6,5) OMEGA(6,6) OMEGA(7,1) OMEGA(7,2) OMEGA(7,3) OMEGA(7,4) OMEGA(7,5) OMEGA(7,6) OMEGA(7,7) OMEGA(8,1) OMEGA(8,2) OMEGA(8,3) OMEGA(8,4) OMEGA(8,5) OMEGA(8,6) OMEGA(8,7) OMEGA(8,8) OMEGA(9,1) OMEGA(9,2) OMEGA(9,3) OMEGA(9,4) OMEGA(9,5) OMEGA(9,6) OMEGA(9,7) OMEGA(9,8) OMEGA(9,9) OMEGA(10,1) OMEGA(10,2) OMEGA(10,3) OMEGA(10,4) OMEGA(10,5) OMEGA(10,6) OMEGA(10,7) OMEGA(10,8) OMEGA(10,9) OMEGA(10,10) OMEGA(11,1) OMEGA(11,2) OMEGA(11,3) OMEGA(11,4) OMEGA(11,5) OMEGA(11,6) OMEGA(11,7) OMEGA(11,8) OMEGA(11,9) OMEGA(11,10) OMEGA(11,11) OBJ + 0 2.00000E-01 3.00000E+00 3.00000E-01 2.00000E+00 5.00000E+00 3.00000E-01 5.00000E-02 6.00000E-01 7.20000E-01 3.00000E-01 1.00000E+02 1.00000E+00 1.00000E+00 1.00000E-02 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 1.00000E-02 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 1.00000E-02 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 2.00000E+01 1.00000E-01 0.00000E+00 3.00000E-02 0.00000E+00 0.00000E+00 1.00000E-01 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 3.00000E-02 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 1.00000E-01 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 4.00000E-02 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 1.00000E-01 1086.3838460923159 + 5 2.29118E-01 2.73796E+00 2.91523E-01 2.13719E+00 6.01452E+00 2.98617E-01 5.20895E-02 6.57805E-01 7.20000E-01 3.01963E-01 1.10326E+02 1.00000E+00 1.18667E+00 1.10321E-02 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 1.05507E-02 0.00000E+00 0.00000E+00 0.00000E+00 0.00000E+00 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HEALTHY +$DATA NM_data_evoPKPD.csv IGNORE=@ +$SUBROUTINE ADVAN13 TRANS1 TOL=6 +$MODEL COMP=(DEPOT,DEFDOSE) ; evolocumab SC depot + COMP=(TDA) ; total evolocumab amount in central + COMP=(TLC,NODOSE) ; total ligand (PCSK9) concentration in central + COMP=(CLDL,NODOSE) ; LDL cholesterol concentration +$PK + +CALLFL=-2 + +;;;;; TMDD PK ;;;;; + +TVKA = THETA(1) +KA = TVKA*EXP(ETA(1)) + +TVV = THETA(2) +V = TVV*EXP(ETA(2)) + +TVCL = THETA(3) +CL = TVCL*EXP(ETA(3)) + +TVKDEG = THETA(4) +KDEG = TVKDEG*EXP(ETA(4)) + +TVPCSK9_0 = THETA(5)*THETA(8)**(HEALTHY) +PCSK9_0 = TVPCSK9_0*EXP(ETA(5)) + +TVKSS = THETA(6) +KSS = TVKSS*EXP(ETA(6)) + +TVKINT = THETA(7) +KINT = TVKINT*EXP(ETA(7)) + +KEL = CL/V + +KSYN = KDEG*PCSK9_0 ; zero-order PCSK9 production rate (nM/day) + +F1 = THETA(9) + +A_0(3) = PCSK9_0 ; change initial condition from default of zero + +;;;;; PD ;;;;; + +TVKOUT = THETA(10) +KOUT = TVKOUT*EXP(ETA(8)) + +TVLDLC_0 = THETA(11) +LDLC_0 = TVLDLC_0*EXP(ETA(9)) + +TVIMAX = THETA(12) +IMAX = TVIMAX*EXP(ETA(10)) + +TVIC50 = THETA(13) +IC50 = TVIC50*EXP(ETA(11)) + +INH0 = (IMAX*PCSK9_0)/(IC50+PCSK9_0) + +KIN = KOUT*(1.0-INH0)*LDLC_0 ; zero-order LDL-C production rate (mg/dL/day) + +A_0(4) = LDLC_0 ; change initial condition from default of zero + +$DES + +;;;;; TMDD PK ;;;;; + +TDC = A(2)/V ; total evolocumab concentration (nM) +FDC = 0.5*((TDC-A(3)-KSS) + SQRT((TDC-A(3)-KSS)**2.0 + 4.0*KSS*TDC)) ; free evolocumab concentration (nM) +FLC = A(3) - (TDC - FDC) ; free PCSK9 concentration (nM) + +DADT(1) = -KA*A(1) ; evolocumab SC depot (nmol) +DADT(2) = KA*A(1) - KEL*FDC*V - (KINT*A(3)*FDC*V)/(KSS+FDC) ; total evolocumab amount in central (nmol) +DADT(3) = KSYN - KDEG*A(3) - ((KINT-KDEG)*FDC*A(3))/(KSS+FDC) ; total PCSK9 concentration in central (nM) + +;;;;; PD ;;;;; + +INH = (IMAX*PCSK9_0)/(IC50+PCSK9_0) +IF (TIME.GT.0) INH = (IMAX*FLC)/(IC50+FLC) + +DADT(4) = KIN - KOUT*(1.0-INH)*A(4) ; LDL-C concentration (mg/dL) + +$ERROR + +TDC2 = A(2)/V ; total evolocumab concentration (nM) +FDC2 = 0.5*((TDC2-A(3)-KSS) + SQRT((TDC2-A(3)-KSS)**2.0 + 4.0*KSS*TDC2)) ; free evolocumab concentration (nM) +FLC2 = A(3) - (TDC2 - FDC2) ; free PCSK9 concentration (nM) + +DRUG=0 +IF(CMT.EQ.2)DRUG=1 + +LIG=0 +IF(CMT.EQ.3)LIG=1 + +LDL=0 +IF(CMT.EQ.4)LDL=1 + +IF(CMT.EQ.2)THEN + IPRED = FDC2*144/1000 ; convert nM to mcg/mL, approximate MW of evolocumab is 144 kDa + IRES = DV-IPRED + W = SQRT(IPRED**2*SIGMA(1,1)+SIGMA(2,2)) + IWRES = IRES/W +ENDIF + +IF(CMT.EQ.3)THEN + IPRED = FLC2 + IRES = DV-IPRED + W = SQRT(IPRED**2*SIGMA(3,3)+SIGMA(4,4)) + IWRES = IRES/W +ENDIF + +IF(CMT.EQ.4)THEN + IPRED = F + IRES = DV-IPRED + W = SQRT(IPRED**2*SIGMA(5,5)+SIGMA(6,6)) + IWRES = IRES/W +ENDIF + +Y1 = IPRED + IPRED*EPS(1) + EPS(2) +Y2 = IPRED + IPRED*EPS(3) + EPS(4) +Y3 = IPRED + IPRED*EPS(5) + EPS(6) + +Y = Y1*DRUG + Y2*LIG + Y3*LDL + +$THETA 0.2 ; KA; 1/day ;first-order evolocumab absorption rate constant + 3 ; V; L ;evolocumab volume of distribution + 0.3 ; CL; L/day ;evolocumab clearance + 2 ; KDEG; 1/day ;first-order PCSK9 degradation rate constant + 5 ; PCSK9_0; nM ;initial PCSK9 concentration + 0.3 ; KSS; nM ;steady-state constant + 0.05 ; KINT; 1/day ;first-order evolocumab-PCSK9 complex elimination rate constant + 0.6 ; PCSK9_0_HEALTHY; none ;fold change in initial PCSK9 conc. for healthy vs. statin-treated + 0.72 FIX ; F1; none ;evolocumab SC bioavailability + 0.3 ; KOUT; 1/day ;first-order elimination rate constant for LDL-C + 100 ; LDLC_0; mg/dL ;baseline LDL-C concentration + 1 FIX ; IMAX; none ;maximal inhibition + 1 ; IC50; nM ;serum unbound PCSK9 concentration associated with half-maximal inhibition +$OMEGA BLOCK(1) + 0.1 ; KA_ +$OMEGA BLOCK(1) + 0.03 ; V_ +$OMEGA BLOCK(1) + 0.1 ; CL_ +$OMEGA BLOCK(1) FIX + 0 ; KDEG_ +$OMEGA BLOCK(1) + 0.03 ; PCSK9_0_ +$OMEGA BLOCK(1) + 0.1 ; KSS_ +$OMEGA BLOCK(1) FIX + 0 ; KINT_ +$OMEGA BLOCK(1) FIX + 0 ; KOUT_ +$OMEGA BLOCK(1) + 0.04 ; LDLC_0_ +$OMEGA BLOCK(1) FIX + 0 ; IMAX_ +$OMEGA BLOCK(1) + 0.1 ; IC50_ +$SIGMA 0.01 ; Evolocumab_Prop + 0 FIX ; Evolocumab_Add + 0.01 ; PCSK9_Prop + 0 FIX ; PCSK9_Add + 0.01 ; LDLC_Prop + 20 ; LDLC_Add +$ESTIMATION METHOD=1 INTER NOHABORT MAXEVAL=9999 PRINT=5 NSIG=1 SIGL=3 +$COVARIANCE PRINT=E MATRIX=S UNCONDITIONAL +;*...............80 Character limit............................................* +$TABLE ID TIME DV CMT MDV EVID IPRED CWRES IWRES ONEHEADER + NOPRINT FILE=sdtab1 +$TABLE ID KA V CL KDEG PCSK9_0 KSS KINT KOUT LDLC_0 IMAX IC50 + ONEHEADER NOPRINT FILE=patab1 ; model parameters +$TABLE ID DOSEMG HEALTHY ONEHEADER NOPRINT FILE=catab1 ; categorical covariates +$TABLE ID ONEHEADER NOPRINT FILE=cotab1 ; continuous covariates + + +NM-TRAN MESSAGES + + WARNINGS AND ERRORS (IF ANY) FOR PROBLEM 1 + + (WARNING 2) NM-TRAN INFERS THAT THE DATA ARE POPULATION. + + (WARNING 3) THERE MAY BE AN ERROR IN THE ABBREVIATED CODE. THE FOLLOWING + ONE OR MORE RANDOM VARIABLES ARE DEFINED WITH "IF" STATEMENTS THAT DO NOT + PROVIDE DEFINITIONS FOR BOTH THE "THEN" AND "ELSE" CASES. IF ALL + CONDITIONS FAIL, THE VALUES OF THESE VARIABLES WILL BE ZERO. + + IPRED IRES W IWRES + + + (WARNING 79) SIGMA IS USED ON THE RIGHT. WITH A SUBSEQUENT RUN, IF AN + INITIAL ESTIMATE OF A DIAGONAL BLOCK OF SIGMA IS TO BE COMPUTED BY + NONMEM, THAT BLOCK WILL BE SET TO AN IDENTITY MATRIX DURING THAT + COMPUTATION. THIS COULD LEAD TO AN ARITHMETIC EXCEPTION.* + + * THE MAXIMUM NUMBER OF WARNINGS OF ONE OR MORE TYPES WAS REACHED. + IT IS POSSIBLE THAT SOME WARNING MESSAGES WERE SUPPRESSED. + +License Registered to: Enhanced Pharmacodynamics LLC +Expiration Date: 14 SEP 2024 +Current Date: 9 APR 2024 +Days until program expires : 155 +1NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM) VERSION 7.4.4 + ORIGINALLY DEVELOPED BY STUART BEAL, LEWIS SHEINER, AND ALISON BOECKMANN + CURRENT DEVELOPERS ARE ROBERT BAUER, ICON DEVELOPMENT SOLUTIONS, + AND ALISON BOECKMANN. IMPLEMENTATION, EFFICIENCY, AND STANDARDIZATION + PERFORMED BY NOUS INFOSYSTEMS. + + PROBLEM NO.: 1 + Simultaneous PKPD of the human anti-PCSK9 mAb evolocumab +0DATA CHECKOUT RUN: NO + DATA SET LOCATED ON UNIT NO.: 2 + THIS UNIT TO BE REWOUND: NO + NO. OF DATA RECS IN DATA SET: 2196 + NO. OF DATA ITEMS IN DATA SET: 11 + ID DATA ITEM IS DATA ITEM NO.: 1 + DEP VARIABLE IS DATA ITEM NO.: 3 + MDV DATA ITEM IS DATA ITEM NO.: 8 +0INDICES PASSED TO SUBROUTINE PRED: + 9 2 4 0 0 6 7 0 0 0 5 +0LABELS FOR DATA ITEMS: + ID TIME DV AMT ADDL II CMT MDV EVID DOSEMG HEALTHY +0(NONBLANK) LABELS FOR PRED-DEFINED ITEMS: + KA V CL KDEG PCSK9_0 KSS KINT KOUT LDLC_0 IMAX IC50 IPRED IWRES +0FORMAT FOR DATA: + (E3.0,E6.0,E10.0,E7.0,E2.0,E3.0,3E2.0,E4.0,E2.0) + + TOT. NO. OF OBS RECS: 2157 + TOT. NO. OF INDIVIDUALS: 39 +0LENGTH OF THETA: 13 +0DEFAULT THETA BOUNDARY TEST OMITTED: NO +0OMEGA HAS BLOCK FORM: + 1 + 0 2 + 0 0 3 + 0 0 0 4 + 0 0 0 0 5 + 0 0 0 0 0 6 + 0 0 0 0 0 0 7 + 0 0 0 0 0 0 0 8 + 0 0 0 0 0 0 0 0 9 + 0 0 0 0 0 0 0 0 0 10 + 0 0 0 0 0 0 0 0 0 0 11 +0DEFAULT OMEGA BOUNDARY TEST OMITTED: NO +0SIGMA HAS BLOCK FORM: + 1 + 0 2 + 0 0 3 + 0 0 0 4 + 0 0 0 0 5 + 0 0 0 0 0 6 +0DEFAULT SIGMA BOUNDARY TEST OMITTED: NO +0INITIAL ESTIMATE OF THETA: + LOWER BOUND INITIAL EST UPPER BOUND + -0.1000E+07 0.2000E+00 0.1000E+07 + -0.1000E+07 0.3000E+01 0.1000E+07 + -0.1000E+07 0.3000E+00 0.1000E+07 + -0.1000E+07 0.2000E+01 0.1000E+07 + -0.1000E+07 0.5000E+01 0.1000E+07 + -0.1000E+07 0.3000E+00 0.1000E+07 + -0.1000E+07 0.5000E-01 0.1000E+07 + -0.1000E+07 0.6000E+00 0.1000E+07 + 0.7200E+00 0.7200E+00 0.7200E+00 + -0.1000E+07 0.3000E+00 0.1000E+07 + -0.1000E+07 0.1000E+03 0.1000E+07 + 0.1000E+01 0.1000E+01 0.1000E+01 + -0.1000E+07 0.1000E+01 0.1000E+07 +0INITIAL ESTIMATE OF OMEGA: + BLOCK SET NO. BLOCK FIXED + 1 NO + 0.1000E+00 + 2 NO + 0.3000E-01 + 3 NO + 0.1000E+00 + 4 YES + 0.0000E+00 + 5 NO + 0.3000E-01 + 6 NO + 0.1000E+00 + 7 YES + 0.0000E+00 + 8 YES + 0.0000E+00 + 9 NO + 0.4000E-01 + 10 YES + 0.0000E+00 + 11 NO + 0.1000E+00 +0INITIAL ESTIMATE OF SIGMA: + BLOCK SET NO. BLOCK FIXED + 1 NO + 0.1000E-01 + 2 YES + 0.0000E+00 + 3 NO + 0.1000E-01 + 4 YES + 0.0000E+00 + 5 NO + 0.1000E-01 + 6 NO + 0.2000E+02 +0COVARIANCE STEP OMITTED: NO + R MATRIX SUBSTITUTED: NO + S MATRIX SUBSTITUTED: YES + EIGENVLS. PRINTED: YES + SPECIAL COMPUTATION: NO + COMPRESSED FORMAT: NO + GRADIENT METHOD USED: NOSLOW + SIGDIGITS ETAHAT (SIGLO): -1 + SIGDIGITS GRADIENTS (SIGL): -1 + EXCLUDE COV FOR FOCE (NOFCOV): NO + TURN OFF Cholesky Transposition of R Matrix (CHOLROFF): NO + KNUTHSUMOFF: -1 + RESUME COV ANALYSIS (RESUME): NO + SIR SAMPLE SIZE (SIRSAMPLE): -1 + NON-LINEARLY TRANSFORM THETAS DURING COV (THBND): 1 + PRECONDTIONING CYCLES (PRECOND): 0 + PRECONDTIONING TYPES (PRECONDS): TOS + FORCED PRECONDTIONING CYCLES (PFCOND):0 + PRECONDTIONING TYPE (PRETYPE): 0 + FORCED POS. DEFINITE SETTING: (FPOSDEF):0 +0TABLES STEP OMITTED: NO + NO. OF TABLES: 4 + SEED NUMBER (SEED): 11456 + RANMETHOD: 3U + MC SAMPLES (ESAMPLE): 300 + WRES SQUARE ROOT TYPE (WRESCHOL): EIGENVALUE +0-- TABLE 1 -- +0RECORDS ONLY: ALL +04 COLUMNS APPENDED: YES + PRINTED: NO + HEADERS: ONE + FILE TO BE FORWARDED: NO + FORMAT: S1PE11.4 + LFORMAT: + RFORMAT: + FIXED_EFFECT_ETAS: +0USER-CHOSEN ITEMS: + ID TIME DV CMT MDV EVID IPRED CWRES IWRES +0-- TABLE 2 -- +0RECORDS ONLY: ALL +04 COLUMNS APPENDED: YES + PRINTED: NO + HEADERS: ONE + FILE TO BE FORWARDED: NO + FORMAT: S1PE11.4 + LFORMAT: + RFORMAT: + FIXED_EFFECT_ETAS: +0USER-CHOSEN ITEMS: + ID KA V CL KDEG PCSK9_0 KSS KINT KOUT LDLC_0 IMAX IC50 +0-- TABLE 3 -- +0RECORDS ONLY: ALL +04 COLUMNS APPENDED: YES + PRINTED: NO + HEADERS: ONE + FILE TO BE FORWARDED: NO + FORMAT: S1PE11.4 + LFORMAT: + RFORMAT: + FIXED_EFFECT_ETAS: +0USER-CHOSEN ITEMS: + ID DOSEMG HEALTHY +0-- TABLE 4 -- +0RECORDS ONLY: ALL +04 COLUMNS APPENDED: YES + PRINTED: NO + HEADERS: ONE + FILE TO BE FORWARDED: NO + FORMAT: S1PE11.4 + LFORMAT: + RFORMAT: + FIXED_EFFECT_ETAS: +0USER-CHOSEN ITEMS: + ID +1DOUBLE PRECISION PREDPP VERSION 7.4.4 + + GENERAL NONLINEAR KINETICS MODEL WITH STIFF/NONSTIFF EQUATIONS (LSODA, ADVAN13) +0MODEL SUBROUTINE USER-SUPPLIED - ID NO. 9999 +0MAXIMUM NO. OF BASIC PK PARAMETERS: 12 +0COMPARTMENT ATTRIBUTES + COMPT. NO. FUNCTION INITIAL ON/OFF DOSE DEFAULT DEFAULT + STATUS ALLOWED ALLOWED FOR DOSE FOR OBS. + 1 DEPOT ON YES YES YES YES + 2 TDA ON YES YES NO NO + 3 TLC ON YES NO NO NO + 4 CLDL ON YES NO NO NO + 5 OUTPUT OFF YES NO NO NO + INITIAL (BASE) TOLERANCE SETTINGS: + NRD (RELATIVE) VALUE(S) OF TOLERANCE: 6 + ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE: 12 +1 + ADDITIONAL PK PARAMETERS - ASSIGNMENT OF ROWS IN GG + COMPT. NO. INDICES + SCALE BIOAVAIL. ZERO-ORDER ZERO-ORDER ABSORB + FRACTION RATE DURATION LAG + 1 * 13 * * * + 2 * * * * * + 3 * - - - - + 4 * - - - - + 5 * - - - - + - PARAMETER IS NOT ALLOWED FOR THIS MODEL + * PARAMETER IS NOT SUPPLIED BY PK SUBROUTINE; + WILL DEFAULT TO ONE IF APPLICABLE +0DATA ITEM INDICES USED BY PRED ARE: + EVENT ID DATA ITEM IS DATA ITEM NO.: 9 + TIME DATA ITEM IS DATA ITEM NO.: 2 + DOSE AMOUNT DATA ITEM IS DATA ITEM NO.: 4 + INTERVAL DATA ITEM IS DATA ITEM NO.: 6 + ADDL. DOSES DATA ITEM IS DATA ITEM NO.: 5 + COMPT. NO. DATA ITEM IS DATA ITEM NO.: 7 + +0PK SUBROUTINE CALLED WITH EVERY EVENT RECORD. + PK SUBROUTINE CALLED AT NONEVENT (ADDITIONAL AND LAGGED) DOSE TIMES. +0PK SUBROUTINE INDICATES THAT COMPARTMENT AMOUNTS ARE INITIALIZED. +0ERROR SUBROUTINE CALLED WITH EVERY EVENT RECORD. +0ERROR SUBROUTINE INDICATES THAT DERIVATIVES OF COMPARTMENT AMOUNTS ARE USED. +0DES SUBROUTINE USES COMPACT STORAGE MODE. +1 + + + #TBLN: 1 + #METH: First Order Conditional Estimation with Interaction + + ESTIMATION STEP OMITTED: NO + ANALYSIS TYPE: POPULATION + NUMBER OF SADDLE POINT RESET ITERATIONS: 0 + GRADIENT METHOD USED: NOSLOW + CONDITIONAL ESTIMATES USED: YES + CENTERED ETA: NO + EPS-ETA INTERACTION: YES + LAPLACIAN OBJ. FUNC.: NO + NO. OF FUNCT. EVALS. ALLOWED: 9999 + NO. OF SIG. FIGURES REQUIRED: 1 + INTERMEDIATE PRINTOUT: YES + ESTIMATE OUTPUT TO MSF: NO + ABORT WITH PRED EXIT CODE 1: NO + IND. OBJ. FUNC. VALUES SORTED: NO + NUMERICAL DERIVATIVE + FILE REQUEST (NUMDER): NONE + MAP (ETAHAT) ESTIMATION METHOD (OPTMAP): 0 + ETA HESSIAN EVALUATION METHOD (ETADER): 0 + INITIAL ETA FOR MAP ESTIMATION (MCETA): 0 + SIGDIGITS FOR MAP ESTIMATION (SIGLO): 3 + GRADIENT SIGDIGITS OF + FIXED EFFECTS PARAMETERS (SIGL): 3 + NOPRIOR SETTING (NOPRIOR): OFF + NOCOV SETTING (NOCOV): OFF + DERCONT SETTING (DERCONT): OFF + FINAL ETA RE-EVALUATION (FNLETA): ON + EXCLUDE NON-INFLUENTIAL (NON-INFL.) ETAS + IN SHRINKAGE (ETASTYPE): NO + NON-INFL. ETA CORRECTION (NONINFETA): OFF + RAW OUTPUT FILE (FILE): psn.ext + EXCLUDE TITLE (NOTITLE): NO + EXCLUDE COLUMN LABELS (NOLABEL): NO + FORMAT FOR ADDITIONAL FILES (FORMAT): S1PE12.5 + PARAMETER ORDER FOR OUTPUTS (ORDER): TSOL + WISHART PRIOR DF INTERPRETATION (WISHTYPE):0 + KNUTHSUMOFF: 0 + INCLUDE LNTWOPI: NO + INCLUDE CONSTANT TERM TO PRIOR (PRIORC): NO + INCLUDE CONSTANT TERM TO OMEGA (ETA) (OLNTWOPI):NO + ADDITIONAL CONVERGENCE TEST (CTYPE=4)?: NO + EM OR BAYESIAN METHOD USED: NONE + + TOLERANCES FOR ESTIMATION/EVALUATION STEP: + NRD (RELATIVE) VALUE(S) OF TOLERANCE: 6 + ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE: 12 + TOLERANCES FOR COVARIANCE STEP: + NRD (RELATIVE) VALUE(S) OF TOLERANCE: 6 + ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE: 12 + TOLERANCES FOR TABLE/SCATTER STEP: + NRD (RELATIVE) VALUE(S) OF TOLERANCE: 6 + ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE: 12 + + THE FOLLOWING LABELS ARE EQUIVALENT + PRED=PREDI + RES=RESI + WRES=WRESI + IWRS=IWRESI + IPRD=IPREDI + IRS=IRESI + + MONITORING OF SEARCH: + + +0ITERATION NO.: 0 OBJECTIVE VALUE: 1086.38384609232 NO. OF FUNC. EVALS.: 17 + CUMULATIVE NO. OF FUNC. EVALS.: 17 + NPARAMETR: 2.0000E-01 3.0000E+00 3.0000E-01 2.0000E+00 5.0000E+00 3.0000E-01 5.0000E-02 6.0000E-01 3.0000E-01 1.0000E+02 + 1.0000E+00 1.0000E-01 3.0000E-02 1.0000E-01 3.0000E-02 1.0000E-01 4.0000E-02 1.0000E-01 1.0000E-02 1.0000E-02 + 1.0000E-02 2.0000E+01 + PARAMETER: 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 + 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 + 1.0000E-01 1.0000E-01 + GRADIENT: 2.6908E+04 5.8204E+04 2.2557E+04 4.7107E+04 8.3792E+04 1.6047E+04 -6.6126E+03 3.7331E+04 9.0146E+02 1.4575E+04 + -1.0856E+03 6.0060E+00 -3.1882E+01 -8.5615E+00 -8.5892E+01 7.9076E+00 -2.5084E+01 -5.8422E+01 -1.8210E+02 -1.1771E+02 + -1.4040E+01 -2.4579E+00 + +0ITERATION NO.: 5 OBJECTIVE VALUE: 967.649232640604 NO. OF FUNC. EVALS.: 249 + CUMULATIVE NO. OF FUNC. EVALS.: 266 + NPARAMETR: 2.2912E-01 2.7380E+00 2.9152E-01 2.1372E+00 6.0145E+00 2.9862E-01 5.2090E-02 6.5780E-01 3.0196E-01 1.1033E+02 + 1.1867E+00 9.0167E-02 4.1977E-02 1.0911E-01 3.4615E-02 1.0385E-01 4.2187E-02 1.3273E-01 1.1032E-02 1.0551E-02 + 1.0117E-02 2.0059E+01 + PARAMETER: 1.1456E-01 9.1265E-02 9.7174E-02 1.0686E-01 1.2029E-01 9.9539E-02 1.0418E-01 1.0963E-01 1.0065E-01 1.1033E-01 + 1.1867E-01 4.8249E-02 2.6796E-01 1.4361E-01 1.7155E-01 1.1891E-01 1.2661E-01 2.4156E-01 1.4911E-01 1.2680E-01 + 1.0580E-01 1.0147E-01 + GRADIENT: -8.9674E+03 -1.1051E+04 -2.0016E+01 -2.8476E+04 -4.3604E+04 -8.6892E+03 -9.3399E+02 -1.8087E+04 -6.6129E+02 -8.0946E+03 + -9.3098E+02 1.5356E+01 2.0790E+00 -3.0529E+00 -4.9098E+01 2.5492E+00 8.5152E+00 -6.4323E+00 -8.6678E+00 -5.1288E+00 + 5.6910E+00 6.0001E+00 + +0ITERATION NO.: 10 OBJECTIVE VALUE: 931.291831807944 NO. OF FUNC. EVALS.: 267 + CUMULATIVE NO. OF FUNC. EVALS.: 533 + NPARAMETR: 2.2698E-01 2.7782E+00 2.8349E-01 2.1131E+00 5.7933E+00 2.8633E-01 5.2697E-02 5.9055E-01 3.0411E-01 1.1269E+02 + 1.3955E+00 7.3344E-02 4.0208E-02 1.1216E-01 4.1563E-02 8.8576E-02 3.8432E-02 1.3474E-01 1.1085E-02 1.0585E-02 + 1.0070E-02 1.9404E+01 + PARAMETER: 1.1349E-01 9.2605E-02 9.4497E-02 1.0566E-01 1.1587E-01 9.5445E-02 1.0539E-01 9.8425E-02 1.0137E-01 1.1269E-01 + 1.3955E-01 -5.5002E-02 2.4643E-01 1.5738E-01 2.6301E-01 3.9343E-02 8.0007E-02 2.4909E-01 1.5151E-01 1.2841E-01 + 1.0351E-01 8.4883E-02 + GRADIENT: -9.0413E+03 -1.0742E+04 -3.8025E+02 -3.0853E+04 -4.7564E+04 -1.0315E+04 3.2016E+03 -2.2914E+04 -2.3788E+02 -7.6835E+03 + -2.6595E+02 3.8438E+00 -7.7978E-01 6.2730E-02 -2.2611E+00 3.1841E+00 3.3118E+00 4.4722E+00 1.4939E+00 -4.1366E+00 + -1.1156E+00 -1.3690E-01 + +0ITERATION NO.: 14 OBJECTIVE VALUE: 925.428463227321 NO. OF FUNC. EVALS.: 205 + CUMULATIVE NO. OF FUNC. EVALS.: 738 + NPARAMETR: 2.2752E-01 2.7189E+00 2.7633E-01 2.1152E+00 5.8852E+00 2.6655E-01 5.2793E-02 5.8211E-01 3.0411E-01 1.1340E+02 + 1.4093E+00 7.0834E-02 4.0264E-02 1.1233E-01 4.2014E-02 8.6357E-02 3.7548E-02 1.2717E-01 1.1073E-02 1.0596E-02 + 1.0078E-02 1.9409E+01 + PARAMETER: 1.1375E-01 9.0438E-02 9.2055E-02 1.0571E-01 1.1765E-01 8.8637E-02 1.0564E-01 9.7075E-02 1.0152E-01 1.1317E-01 + 1.4084E-01 -7.1854E-02 2.4756E-01 1.5827E-01 2.6818E-01 2.9822E-02 6.8917E-02 2.2139E-01 1.5097E-01 1.2895E-01 + 1.0386E-01 8.5023E-02 + GRADIENT: -1.1556E+01 -4.3750E+03 -6.5510E+01 -7.0982E+02 -1.5508E+02 -4.8674E+03 4.1906E+03 1.3916E+02 4.7961E+03 -4.4800E+03 + -4.1346E+01 1.2856E+00 8.4176E-01 3.3015E-01 -6.9203E-01 8.7891E+00 1.5987E+00 2.0590E+00 1.0945E+00 -7.8371E-01 + -3.0099E-01 7.8185E-02 + NUMSIGDIG: 2.9 1.4 2.0 2.0 2.0 1.4 1.9 1.9 1.5 1.4 + 1.9 0.9 1.4 1.7 1.8 0.2 0.9 0.9 2.4 2.6 + 2.7 2.7 + + #TERM: +0MINIMIZATION TERMINATED + DUE TO ROUNDING ERRORS (ERROR=134) + NO. OF FUNCTION EVALUATIONS USED: 738 + NO. OF SIG. DIGITS IN FINAL EST.: 0.2 + ADDITIONAL PROBLEMS OCCURRED WITH THE MINIMIZATION. + REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM ONLY + AFTER CHECKING THAT THE COVARIANCE STEP PRODUCES REASONABLE OUTPUT. + + ETABAR IS THE ARITHMETIC MEAN OF THE ETA-ESTIMATES, + AND THE P-VALUE IS GIVEN FOR THE NULL HYPOTHESIS THAT THE TRUE MEAN IS 0. + + ETABAR: 1.8279E-03 -1.6584E-02 3.1212E-03 0.0000E+00 6.9994E-03 -2.0634E-02 0.0000E+00 0.0000E+00 -3.9213E-04 0.0000E+00 + 7.3180E-03 + SE: 3.9614E-02 2.8113E-02 4.5552E-02 0.0000E+00 3.2497E-02 4.3668E-02 0.0000E+00 0.0000E+00 3.0199E-02 0.0000E+00 + 4.7335E-02 + N: 39 39 39 39 39 39 39 39 39 39 + 39 + + P VAL.: 9.6320E-01 5.5526E-01 9.4537E-01 1.0000E+00 8.2946E-01 6.3656E-01 1.0000E+00 1.0000E+00 9.8964E-01 1.0000E+00 + 8.7714E-01 + + ETASHRINKSD(%) 5.8857E+00 1.1401E+01 1.4024E+01 1.0000E+02 1.0000E-10 6.2838E+00 1.0000E+02 1.0000E+02 1.4564E+00 1.0000E+02 + 1.6124E+01 + ETASHRINKVR(%) 1.1425E+01 2.1502E+01 2.6081E+01 1.0000E+02 1.0000E-10 1.2173E+01 1.0000E+02 1.0000E+02 2.8916E+00 1.0000E+02 + 2.9648E+01 + EBVSHRINKSD(%) 6.9986E+00 1.2232E+01 1.5924E+01 0.0000E+00 1.3891E+00 1.6127E+00 0.0000E+00 0.0000E+00 1.5444E+00 0.0000E+00 + 1.5751E+01 + EBVSHRINKVR(%) 1.3507E+01 2.2968E+01 2.9312E+01 0.0000E+00 2.7588E+00 3.1995E+00 0.0000E+00 0.0000E+00 3.0649E+00 0.0000E+00 + 2.9022E+01 + EPSSHRINKSD(%) 6.5409E+00 1.0000E+02 5.9585E+00 1.0000E+02 4.2882E+00 4.2882E+00 + EPSSHRINKVR(%) 1.2654E+01 1.0000E+02 1.1562E+01 1.0000E+02 8.3926E+00 8.3926E+00 + + + TOTAL DATA POINTS NORMALLY DISTRIBUTED (N): 2157 + N*LOG(2PI) CONSTANT TO OBJECTIVE FUNCTION: 3964.3008322449577 + OBJECTIVE FUNCTION VALUE WITHOUT CONSTANT: 925.42846322732066 + OBJECTIVE FUNCTION VALUE WITH CONSTANT: 4889.7292954722780 + REPORTED OBJECTIVE FUNCTION DOES NOT CONTAIN CONSTANT + + TOTAL EFFECTIVE ETAS (NIND*NETA): 273 + + #TERE: + Elapsed estimation time in seconds: 697.22 + Elapsed covariance time in seconds: 38.65 + Elapsed postprocess time in seconds: 1.93 +1 + + + + + + + + + + + + + + + + + + + + + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + #OBJT:************** MINIMUM VALUE OF OBJECTIVE FUNCTION ******************** + ******************** ******************** + ************************************************************************************************************************ + + + + + + + #OBJV:******************************************** 925.428 ************************************************** +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** FINAL PARAMETER ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + + THETA - VECTOR OF FIXED EFFECTS PARAMETERS ********* + + + TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 TH 7 TH 8 TH 9 TH10 TH11 TH12 + TH13 + + 2.28E-01 2.71E+00 2.76E-01 2.11E+00 5.88E+00 2.66E-01 5.28E-02 5.82E-01 7.20E-01 3.05E-01 1.13E+02 1.00E+00 + 1.41E+00 + + + + OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ******** + + + ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA7 ETA8 ETA9 ET10 ET11 + + ETA1 ++ 7.09E-02 + + ETA2 ++ 0.00E+00 4.03E-02 + + ETA3 ++ 0.00E+00 0.00E+00 1.12E-01 + + ETA4 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 + + ETA5 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 4.20E-02 + + ETA6 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 8.69E-02 + + ETA7 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 + + ETA8 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 + + ETA9 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 3.76E-02 + + ET10 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 + + ET11 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 1.27E-01 + + + + SIGMA - COV MATRIX FOR RANDOM EFFECTS - EPSILONS **** + + + EPS1 EPS2 EPS3 EPS4 EPS5 EPS6 + + EPS1 ++ 1.11E-02 + + EPS2 ++ 0.00E+00 0.00E+00 + +1 + + EPS1 EPS2 EPS3 EPS4 EPS5 EPS6 + + EPS3 ++ 0.00E+00 0.00E+00 1.06E-02 + + EPS4 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 + + EPS5 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 1.01E-02 + + EPS6 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 1.94E+01 + +1 + + + OMEGA - CORR MATRIX FOR RANDOM EFFECTS - ETAS ******* + + + ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA7 ETA8 ETA9 ET10 ET11 + + ETA1 ++ 2.66E-01 + + ETA2 ++ 0.00E+00 2.01E-01 + + ETA3 ++ 0.00E+00 0.00E+00 3.35E-01 + + ETA4 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 + + ETA5 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 2.05E-01 + + ETA6 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 2.95E-01 + + ETA7 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 + + ETA8 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 + + ETA9 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 1.94E-01 + + ET10 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 + + ET11 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 3.57E-01 + + + + SIGMA - CORR MATRIX FOR RANDOM EFFECTS - EPSILONS *** + + + EPS1 EPS2 EPS3 EPS4 EPS5 EPS6 + + EPS1 ++ 1.05E-01 + + EPS2 ++ 0.00E+00 0.00E+00 + + EPS3 ++ 0.00E+00 0.00E+00 1.03E-01 + + EPS4 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 + + EPS5 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 1.00E-01 + + EPS6 ++ 0.00E+00 0.00E+00 0.00E+00 0.00E+00 0.00E+00 4.41E+00 + +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** STANDARD ERROR OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + + THETA - VECTOR OF FIXED EFFECTS PARAMETERS ********* + + + TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 TH 7 TH 8 TH 9 TH10 TH11 TH12 + TH13 + + 1.74E-02 1.54E-01 3.70E-02 6.66E-02 4.28E-01 1.92E-02 5.45E-04 5.30E-02 ......... 7.20E-03 5.33E+00 ......... + 1.77E-01 + + + + OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ******** + + + ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA7 ETA8 ETA9 ET10 ET11 + + ETA1 ++ 3.76E-02 + + ETA2 ++ ......... 2.38E-02 + + ETA3 ++ ......... ......... 4.82E-02 + + ETA4 ++ ......... ......... ......... ......... + + ETA5 ++ ......... ......... ......... ......... 2.18E-02 + + ETA6 ++ ......... ......... ......... ......... ......... 3.67E-02 + + ETA7 ++ ......... ......... ......... ......... ......... ......... ......... + + ETA8 ++ ......... ......... ......... ......... ......... ......... ......... ......... + + ETA9 ++ ......... ......... ......... ......... ......... ......... ......... ......... 1.35E-02 + + ET10 ++ ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... + + ET11 ++ ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 5.35E-02 + + + + SIGMA - COV MATRIX FOR RANDOM EFFECTS - EPSILONS **** + + + EPS1 EPS2 EPS3 EPS4 EPS5 EPS6 + + EPS1 ++ 1.08E-03 + + EPS2 ++ ......... ......... + +1 + + EPS1 EPS2 EPS3 EPS4 EPS5 EPS6 + + EPS3 ++ ......... ......... 9.00E-04 + + EPS4 ++ ......... ......... ......... ......... + + EPS5 ++ ......... ......... ......... ......... 1.54E-03 + + EPS6 ++ ......... ......... ......... ......... ......... 6.02E+00 + +1 + + + OMEGA - CORR MATRIX FOR RANDOM EFFECTS - ETAS ******* + + + ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA7 ETA8 ETA9 ET10 ET11 + + ETA1 ++ 7.06E-02 + + ETA2 ++ ......... 5.93E-02 + + ETA3 ++ ......... ......... 7.19E-02 + + ETA4 ++ ......... ......... ......... ......... + + ETA5 ++ ......... ......... ......... ......... 5.31E-02 + + ETA6 ++ ......... ......... ......... ......... ......... 6.22E-02 + + ETA7 ++ ......... ......... ......... ......... ......... ......... ......... + + ETA8 ++ ......... ......... ......... ......... ......... ......... ......... ......... + + ETA9 ++ ......... ......... ......... ......... ......... ......... ......... ......... 3.47E-02 + + ET10 ++ ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... + + ET11 ++ ......... ......... ......... ......... ......... ......... ......... ......... ......... ......... 7.49E-02 + + + + SIGMA - CORR MATRIX FOR RANDOM EFFECTS - EPSILONS *** + + + EPS1 EPS2 EPS3 EPS4 EPS5 EPS6 + + EPS1 ++ 5.15E-03 + + EPS2 ++ ......... ......... + + EPS3 ++ ......... ......... 4.37E-03 + + EPS4 ++ ......... ......... ......... ......... + + EPS5 ++ ......... ......... ......... ......... 7.69E-03 + + EPS6 ++ ......... ......... ......... ......... ......... 6.83E-01 + +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** COVARIANCE MATRIX OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + TH 1 | TH 1 TH 2 | TH 1 TH 2 | TH 2 TH 3 | TH 1 TH 3 | TH 2 TH 3 | TH 3 TH 4 | TH 1 + 3.04E-04 -4.44E-04 2.36E-02 -1.94E-05 2.25E-03 1.37E-03 3.18E-04 + + TH 4 | TH 2 TH 4 | TH 3 TH 4 | TH 4 TH 5 | TH 1 TH 5 | TH 2 TH 5 | TH 3 TH 5 | TH 4 + -6.29E-03 -1.61E-03 4.43E-03 -2.44E-03 1.78E-02 6.11E-03 -1.44E-02 + + TH 5 | TH 5 TH 6 | TH 1 TH 6 | TH 2 TH 6 | TH 3 TH 6 | TH 4 TH 6 | TH 5 TH 6 | TH 6 + 1.83E-01 -2.65E-04 9.64E-04 2.16E-04 -6.80E-04 3.63E-03 3.68E-04 + + TH 7 | TH 1 TH 7 | TH 2 TH 7 | TH 3 TH 7 | TH 4 TH 7 | TH 5 TH 7 | TH 6 TH 7 | TH 7 + 3.42E-07 -2.50E-05 -5.61E-06 1.63E-05 -5.72E-05 -3.00E-06 2.98E-07 + + TH 8 | TH 1 TH 8 | TH 2 TH 8 | TH 3 TH 8 | TH 4 TH 8 | TH 5 TH 8 | TH 6 TH 8 | TH 7 + -1.66E-04 1.26E-03 -4.24E-04 2.95E-04 -1.26E-02 -4.25E-05 7.22E-06 + + TH 8 | TH 8 TH10 | TH 1 TH10 | TH 2 TH10 | TH 3 TH10 | TH 4 TH10 | TH 5 TH10 | TH 6 + 2.81E-03 -3.80E-06 -2.49E-04 -1.11E-04 2.10E-04 -5.58E-04 -1.89E-05 + + TH10 | TH 7 TH10 | TH 8 TH10 | TH10 TH11 | TH 1 TH11 | TH 2 TH11 | TH 3 TH11 | TH 4 + 1.05E-06 -2.45E-06 5.19E-05 -5.41E-02 -1.16E-01 -6.58E-02 8.62E-02 + + TH11 | TH 5 TH11 | TH 6 TH11 | TH 7 TH11 | TH 8 TH11 | TH10 TH11 | TH11 TH13 | TH 1 + -1.09E-01 -3.02E-03 9.00E-04 1.04E-01 8.52E-03 2.84E+01 1.65E-03 + + TH13 | TH 2 TH13 | TH 3 TH13 | TH 4 TH13 | TH 5 TH13 | TH 6 TH13 | TH 7 TH13 | TH 8 + -5.69E-03 1.63E-03 1.88E-03 -7.27E-03 -8.24E-04 -2.27E-06 -3.17E-03 + + TH13 | TH10 TH13 | TH11 TH13 | TH13 OM0101 | TH 1 OM0101 | TH 2 OM0101 | TH 3 OM0101 | TH 4 + -1.75E-05 -5.34E-01 3.13E-02 2.50E-04 3.24E-04 3.15E-04 3.05E-04 + + OM0101 | TH 5 OM0101 | TH 6 OM0101 | TH 7 OM0101 | TH 8 OM0101 | TH10 OM0101 | TH11 OM0101 | TH13 + 5.64E-04 -2.31E-04 3.19E-06 -3.88E-04 3.27E-06 -4.43E-02 2.71E-03 + + OM0101 | OM0101 OM0202 | TH 1 OM0202 | TH 2 OM0202 | TH 3 OM0202 | TH 4 OM0202 | TH 5 OM0202 | TH 6 + 1.41E-03 -2.18E-04 8.28E-04 1.38E-04 -6.26E-04 1.92E-03 2.71E-04 + + OM0202 | TH 7 OM0202 | TH 8 OM0202 | TH10 OM0202 | TH11 OM0202 | TH13 OM0202 | OM0101 OM0202 | OM0202 + -2.89E-06 2.25E-05 -1.26E-05 1.03E-02 -9.73E-04 -4.80E-04 5.67E-04 + + OM0303 | TH 1 OM0303 | TH 2 OM0303 | TH 3 OM0303 | TH 4 OM0303 | TH 5 OM0303 | TH 6 OM0303 | TH 7 + 3.87E-05 -5.76E-04 -1.57E-04 1.32E-04 -2.63E-04 2.53E-06 2.73E-07 + + OM0303 | TH 8 OM0303 | TH10 OM0303 | TH11 OM0303 | TH13 OM0303 | OM0101 OM0303 | OM0202 OM0303 | OM0303 + -1.53E-04 5.77E-06 -3.22E-02 5.95E-04 -4.35E-05 -9.38E-05 2.32E-03 + + OM0505 | TH 1 OM0505 | TH 2 OM0505 | TH 3 OM0505 | TH 4 OM0505 | TH 5 OM0505 | TH 6 OM0505 | TH 7 + 1.39E-04 -3.26E-04 1.08E-04 4.22E-05 -4.30E-04 -3.04E-05 -1.48E-06 + + OM0505 | TH 8 OM0505 | TH10 OM0505 | TH11 OM0505 | TH13 OM0505 | OM0101 OM0505 | OM0202 OM0505 | OM0303 + -5.84E-04 2.70E-05 -6.14E-02 1.90E-03 1.71E-04 4.84E-06 1.55E-04 + + OM0505 | OM0505 OM0606 | TH 1 OM0606 | TH 2 OM0606 | TH 3 OM0606 | TH 4 OM0606 | TH 5 OM0606 | TH 6 + 4.74E-04 -9.52E-05 1.04E-04 3.29E-04 -1.40E-04 4.25E-03 1.66E-04 + + OM0606 | TH 7 OM0606 | TH 8 OM0606 | TH10 OM0606 | TH11 OM0606 | TH13 OM0606 | OM0101 OM0606 | OM0202 + -3.37E-06 -2.31E-04 7.33E-06 -1.10E-02 3.96E-04 -2.57E-04 1.52E-04 + + OM0606 | OM0303 OM0606 | OM0505 OM0606 | OM0606 OM0909 | TH 1 OM0909 | TH 2 OM0909 | TH 3 OM0909 | TH 4 + 3.39E-05 6.31E-05 1.35E-03 -3.29E-05 3.43E-04 7.99E-05 -2.27E-04 + + OM0909 | TH 5 OM0909 | TH 6 OM0909 | TH 7 OM0909 | TH 8 OM0909 | TH10 OM0909 | TH11 OM0909 | TH13 + 1.26E-03 3.51E-05 -3.66E-07 1.79E-04 -2.72E-05 4.61E-03 -5.41E-04 + + OM0909 | OM0101 OM0909 | OM0202 OM0909 | OM0303 OM0909 | OM0505 OM0909 | OM0606 OM0909 | OM0909 OM1111 | TH 1 + -4.00E-06 -3.64E-05 8.80E-05 -1.48E-04 1.62E-05 1.81E-04 5.91E-05 + + OM1111 | TH 2 OM1111 | TH 3 OM1111 | TH 4 OM1111 | TH 5 OM1111 | TH 6 OM1111 | TH 7 OM1111 | TH 8 + -8.87E-04 -1.48E-05 6.56E-04 -1.51E-03 1.20E-05 -7.26E-06 -7.27E-04 + + OM1111 | TH10 OM1111 | TH11 OM1111 | TH13 OM1111 | OM0101 OM1111 | OM0202 OM1111 | OM0303 OM1111 | OM0505 + 6.03E-05 -3.26E-02 3.05E-03 1.34E-04 1.29E-04 -5.77E-04 2.12E-04 + + OM1111 | OM0606 OM1111 | OM0909 OM1111 | OM1111 SG0101 | TH 1 SG0101 | TH 2 SG0101 | TH 3 SG0101 | TH 4 + 2.29E-04 -1.73E-04 2.86E-03 4.76E-06 -4.67E-05 -1.36E-05 3.36E-05 + + SG0101 | TH 5 SG0101 | TH 6 SG0101 | TH 7 SG0101 | TH 8 SG0101 | TH10 SG0101 | TH11 SG0101 | TH13 + -1.24E-04 -6.87E-06 1.50E-07 -4.53E-06 2.73E-06 -3.96E-05 4.03E-05 + + SG0101 | OM0101 SG0101 | OM0202 SG0101 | OM0303 SG0101 | OM0505 SG0101 | OM0606 SG0101 | OM0909 SG0101 | OM1111 + 1.38E-05 -9.32E-06 1.38E-05 5.31E-06 -9.11E-06 -2.67E-06 9.88E-07 + + SG0101 | SG0101 SG0303 | TH 1 SG0303 | TH 2 SG0303 | TH 3 SG0303 | TH 4 SG0303 | TH 5 SG0303 | TH 6 + 1.18E-06 2.87E-06 -2.38E-05 5.85E-06 1.42E-06 -1.27E-05 1.45E-07 + + SG0303 | TH 7 SG0303 | TH 8 SG0303 | TH10 SG0303 | TH11 SG0303 | TH13 SG0303 | OM0101 SG0303 | OM0202 + -8.57E-09 -4.72E-06 -8.49E-07 -1.38E-03 5.46E-05 -4.47E-06 1.98E-06 + + SG0303 | OM0303 SG0303 | OM0505 SG0303 | OM0606 SG0303 | OM0909 SG0303 | OM1111 SG0303 | SG0101 SG0303 | SG0303 + -1.17E-05 8.59E-07 8.93E-06 -1.13E-06 8.61E-06 -1.68E-07 8.10E-07 + + SG0505 | TH 1 SG0505 | TH 2 SG0505 | TH 3 SG0505 | TH 4 SG0505 | TH 5 SG0505 | TH 6 SG0505 | TH 7 + -1.08E-06 3.33E-05 8.82E-06 -1.03E-05 1.37E-04 5.13E-07 -7.94E-08 + + SG0505 | TH 8 SG0505 | TH10 SG0505 | TH11 SG0505 | TH13 SG0505 | OM0101 SG0505 | OM0202 SG0505 | OM0303 + 8.90E-07 1.44E-07 5.00E-04 -6.24E-05 -6.43E-06 -2.71E-06 9.93E-06 + + SG0505 | OM0505 SG0505 | OM0606 SG0505 | OM0909 SG0505 | OM1111 SG0505 | SG0101 SG0505 | SG0303 SG0505 | SG0505 + -1.04E-06 1.91E-05 7.02E-06 -2.03E-05 3.07E-08 -1.67E-07 2.38E-06 + + SG0606 | TH 1 SG0606 | TH 2 SG0606 | TH 3 SG0606 | TH 4 SG0606 | TH 5 SG0606 | TH 6 SG0606 | TH 7 + -2.60E-02 -6.74E-02 -5.70E-02 4.21E-02 -4.92E-01 7.34E-03 -5.35E-05 + + SG0606 | TH 8 SG0606 | TH10 SG0606 | TH11 SG0606 | TH13 SG0606 | OM0101 SG0606 | OM0202 SG0606 | OM0303 + 5.07E-02 -1.56E-04 1.03E+01 -2.72E-01 -6.95E-02 2.79E-02 -3.33E-02 + + SG0606 | OM0505 SG0606 | OM0606 SG0606 | OM0909 SG0606 | OM1111 SG0606 | SG0101 SG0606 | SG0303 SG0606 | SG0505 + -2.78E-02 -2.42E-02 -1.97E-02 5.02E-02 -1.13E-03 -1.38E-04 -5.80E-03 + + SG0606 | SG0606 + 3.62E+01 +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** CORRELATION MATRIX OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + TH 1 | TH 1 TH 2 | TH 1 TH 2 | TH 2 TH 3 | TH 1 TH 3 | TH 2 TH 3 | TH 3 TH 4 | TH 1 + 1.74E-02 -1.66E-01 1.54E-01 -3.02E-02 3.95E-01 3.70E-02 2.74E-01 + + TH 4 | TH 2 TH 4 | TH 3 TH 4 | TH 4 TH 5 | TH 1 TH 5 | TH 2 TH 5 | TH 3 TH 5 | TH 4 + -6.16E-01 -6.54E-01 6.66E-02 -3.28E-01 2.71E-01 3.87E-01 -5.05E-01 + + TH 5 | TH 5 TH 6 | TH 1 TH 6 | TH 2 TH 6 | TH 3 TH 6 | TH 4 TH 6 | TH 5 TH 6 | TH 6 + 4.28E-01 -7.94E-01 3.27E-01 3.05E-01 -5.33E-01 4.43E-01 1.92E-02 + + TH 7 | TH 1 TH 7 | TH 2 TH 7 | TH 3 TH 7 | TH 4 TH 7 | TH 5 TH 7 | TH 6 TH 7 | TH 7 + 3.60E-02 -2.99E-01 -2.78E-01 4.48E-01 -2.45E-01 -2.87E-01 5.45E-04 + + TH 8 | TH 1 TH 8 | TH 2 TH 8 | TH 3 TH 8 | TH 4 TH 8 | TH 5 TH 8 | TH 6 TH 8 | TH 7 + -1.79E-01 1.54E-01 -2.16E-01 8.34E-02 -5.55E-01 -4.18E-02 2.50E-01 + + TH 8 | TH 8 TH10 | TH 1 TH10 | TH 2 TH10 | TH 3 TH10 | TH 4 TH10 | TH 5 TH10 | TH 6 + 5.30E-02 -3.03E-02 -2.25E-01 -4.17E-01 4.38E-01 -1.81E-01 -1.37E-01 + + TH10 | TH 7 TH10 | TH 8 TH10 | TH10 TH11 | TH 1 TH11 | TH 2 TH11 | TH 3 TH11 | TH 4 + 2.67E-01 -6.41E-03 7.20E-03 -5.83E-01 -1.42E-01 -3.34E-01 2.43E-01 + + TH11 | TH 5 TH11 | TH 6 TH11 | TH 7 TH11 | TH 8 TH11 | TH10 TH11 | TH11 TH13 | TH 1 + -4.79E-02 -2.95E-02 3.10E-01 3.69E-01 2.22E-01 5.33E+00 5.35E-01 + + TH13 | TH 2 TH13 | TH 3 TH13 | TH 4 TH13 | TH 5 TH13 | TH 6 TH13 | TH 7 TH13 | TH 8 + -2.10E-01 2.50E-01 1.60E-01 -9.61E-02 -2.43E-01 -2.35E-02 -3.38E-01 + + TH13 | TH10 TH13 | TH11 TH13 | TH13 OM0101 | TH 1 OM0101 | TH 2 OM0101 | TH 3 OM0101 | TH 4 + -1.37E-02 -5.67E-01 1.77E-01 3.81E-01 5.61E-02 2.26E-01 1.22E-01 + + OM0101 | TH 5 OM0101 | TH 6 OM0101 | TH 7 OM0101 | TH 8 OM0101 | TH10 OM0101 | TH11 OM0101 | TH13 + 3.51E-02 -3.20E-01 1.56E-01 -1.94E-01 1.21E-02 -2.21E-01 4.07E-01 + + OM0101 | OM0101 OM0202 | TH 1 OM0202 | TH 2 OM0202 | TH 3 OM0202 | TH 4 OM0202 | TH 5 OM0202 | TH 6 + 3.76E-02 -5.25E-01 2.26E-01 1.57E-01 -3.95E-01 1.88E-01 5.94E-01 + + OM0202 | TH 7 OM0202 | TH 8 OM0202 | TH10 OM0202 | TH11 OM0202 | TH13 OM0202 | OM0101 OM0202 | OM0202 + -2.22E-01 1.78E-02 -7.35E-02 8.15E-02 -2.31E-01 -5.36E-01 2.38E-02 + + OM0303 | TH 1 OM0303 | TH 2 OM0303 | TH 3 OM0303 | TH 4 OM0303 | TH 5 OM0303 | TH 6 OM0303 | TH 7 + 4.61E-02 -7.79E-02 -8.80E-02 4.11E-02 -1.28E-02 2.74E-03 1.04E-02 + + OM0303 | TH 8 OM0303 | TH10 OM0303 | TH11 OM0303 | TH13 OM0303 | OM0101 OM0303 | OM0202 OM0303 | OM0303 + -5.97E-02 1.66E-02 -1.25E-01 6.97E-02 -2.40E-02 -8.18E-02 4.82E-02 + + OM0505 | TH 1 OM0505 | TH 2 OM0505 | TH 3 OM0505 | TH 4 OM0505 | TH 5 OM0505 | TH 6 OM0505 | TH 7 + 3.66E-01 -9.75E-02 1.34E-01 2.91E-02 -4.62E-02 -7.28E-02 -1.25E-01 + + OM0505 | TH 8 OM0505 | TH10 OM0505 | TH11 OM0505 | TH13 OM0505 | OM0101 OM0505 | OM0202 OM0505 | OM0303 + -5.05E-01 1.72E-01 -5.29E-01 4.92E-01 2.09E-01 9.33E-03 1.47E-01 + + OM0505 | OM0505 OM0606 | TH 1 OM0606 | TH 2 OM0606 | TH 3 OM0606 | TH 4 OM0606 | TH 5 OM0606 | TH 6 + 2.18E-02 -1.49E-01 1.84E-02 2.42E-01 -5.75E-02 2.71E-01 2.36E-01 + + OM0606 | TH 7 OM0606 | TH 8 OM0606 | TH10 OM0606 | TH11 OM0606 | TH13 OM0606 | OM0101 OM0606 | OM0202 + -1.68E-01 -1.19E-01 2.77E-02 -5.65E-02 6.11E-02 -1.86E-01 1.74E-01 + + OM0606 | OM0303 OM0606 | OM0505 OM0606 | OM0606 OM0909 | TH 1 OM0909 | TH 2 OM0909 | TH 3 OM0909 | TH 4 + 1.92E-02 7.89E-02 3.67E-02 -1.40E-01 1.66E-01 1.61E-01 -2.53E-01 + + OM0909 | TH 5 OM0909 | TH 6 OM0909 | TH 7 OM0909 | TH 8 OM0909 | TH10 OM0909 | TH11 OM0909 | TH13 + 2.19E-01 1.36E-01 -4.98E-02 2.51E-01 -2.81E-01 6.43E-02 -2.27E-01 + + OM0909 | OM0101 OM0909 | OM0202 OM0909 | OM0303 OM0909 | OM0505 OM0909 | OM0606 OM0909 | OM0909 OM1111 | TH 1 + -7.90E-03 -1.14E-01 1.36E-01 -5.04E-01 3.29E-02 1.35E-02 6.34E-02 + + OM1111 | TH 2 OM1111 | TH 3 OM1111 | TH 4 OM1111 | TH 5 OM1111 | TH 6 OM1111 | TH 7 OM1111 | TH 8 + -1.08E-01 -7.48E-03 1.84E-01 -6.62E-02 1.17E-02 -2.49E-01 -2.56E-01 + + OM1111 | TH10 OM1111 | TH11 OM1111 | TH13 OM1111 | OM0101 OM1111 | OM0202 OM1111 | OM0303 OM1111 | OM0505 + 1.57E-01 -1.14E-01 3.23E-01 6.67E-02 1.01E-01 -2.24E-01 1.82E-01 + + OM1111 | OM0606 OM1111 | OM0909 OM1111 | OM1111 SG0101 | TH 1 SG0101 | TH 2 SG0101 | TH 3 SG0101 | TH 4 + 1.16E-01 -2.40E-01 5.35E-02 2.52E-01 -2.80E-01 -3.39E-01 4.66E-01 + + SG0101 | TH 5 SG0101 | TH 6 SG0101 | TH 7 SG0101 | TH 8 SG0101 | TH10 SG0101 | TH11 SG0101 | TH13 + -2.68E-01 -3.30E-01 2.54E-01 -7.87E-02 3.49E-01 -6.86E-03 2.10E-01 + + SG0101 | OM0101 SG0101 | OM0202 SG0101 | OM0303 SG0101 | OM0505 SG0101 | OM0606 SG0101 | OM0909 SG0101 | OM1111 + 3.39E-01 -3.61E-01 2.65E-01 2.25E-01 -2.29E-01 -1.83E-01 1.70E-02 + + SG0101 | SG0101 SG0303 | TH 1 SG0303 | TH 2 SG0303 | TH 3 SG0303 | TH 4 SG0303 | TH 5 SG0303 | TH 6 + 1.08E-03 1.83E-01 -1.72E-01 1.76E-01 2.37E-02 -3.29E-02 8.40E-03 + + SG0303 | TH 7 SG0303 | TH 8 SG0303 | TH10 SG0303 | TH11 SG0303 | TH13 SG0303 | OM0101 SG0303 | OM0202 + -1.75E-02 -9.89E-02 -1.31E-01 -2.88E-01 3.43E-01 -1.32E-01 9.24E-02 + + SG0303 | OM0303 SG0303 | OM0505 SG0303 | OM0606 SG0303 | OM0909 SG0303 | OM1111 SG0303 | SG0101 SG0303 | SG0303 + -2.71E-01 4.38E-02 2.70E-01 -9.34E-02 1.79E-01 -1.72E-01 9.00E-04 + + SG0505 | TH 1 SG0505 | TH 2 SG0505 | TH 3 SG0505 | TH 4 SG0505 | TH 5 SG0505 | TH 6 SG0505 | TH 7 + -4.02E-02 1.41E-01 1.55E-01 -1.00E-01 2.08E-01 1.74E-02 -9.43E-02 + + SG0505 | TH 8 SG0505 | TH10 SG0505 | TH11 SG0505 | TH13 SG0505 | OM0101 SG0505 | OM0202 SG0505 | OM0303 + 1.09E-02 1.29E-02 6.08E-02 -2.29E-01 -1.11E-01 -7.39E-02 1.34E-01 + + SG0505 | OM0505 SG0505 | OM0606 SG0505 | OM0909 SG0505 | OM1111 SG0505 | SG0101 SG0505 | SG0303 SG0505 | SG0505 + -3.08E-02 3.37E-01 3.38E-01 -2.46E-01 1.83E-02 -1.20E-01 1.54E-03 + + SG0606 | TH 1 SG0606 | TH 2 SG0606 | TH 3 SG0606 | TH 4 SG0606 | TH 5 SG0606 | TH 6 SG0606 | TH 7 + -2.47E-01 -7.29E-02 -2.56E-01 1.05E-01 -1.91E-01 6.36E-02 -1.63E-02 + + SG0606 | TH 8 SG0606 | TH10 SG0606 | TH11 SG0606 | TH13 SG0606 | OM0101 SG0606 | OM0202 SG0606 | OM0303 + 1.59E-01 -3.60E-03 3.21E-01 -2.55E-01 -3.07E-01 1.95E-01 -1.15E-01 + + SG0606 | OM0505 SG0606 | OM0606 SG0606 | OM0909 SG0606 | OM1111 SG0606 | SG0101 SG0606 | SG0303 SG0606 | SG0505 + -2.12E-01 -1.10E-01 -2.43E-01 1.56E-01 -1.72E-01 -2.55E-02 -6.24E-01 + + SG0606 | SG0606 + 6.02E+00 +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** INVERSE COVARIANCE MATRIX OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + TH 1 | TH 1 TH 2 | TH 1 TH 2 | TH 2 TH 3 | TH 1 TH 3 | TH 2 TH 3 | TH 3 TH 4 | TH 1 + 4.77E+06 -4.27E+03 1.00E+02 -5.27E+04 4.06E+01 3.21E+03 -1.47E+04 + + TH 4 | TH 2 TH 4 | TH 3 TH 4 | TH 4 TH 5 | TH 1 TH 5 | TH 2 TH 5 | TH 3 TH 5 | TH 4 + 1.14E+02 1.16E+03 1.24E+03 -2.27E+03 -7.61E+00 7.23E+01 6.22E+01 + + TH 5 | TH 5 TH 6 | TH 1 TH 6 | TH 2 TH 6 | TH 3 TH 6 | TH 4 TH 6 | TH 5 TH 6 | TH 6 + 2.64E+01 3.59E+06 -3.18E+03 -4.03E+04 -1.09E+04 -1.84E+03 2.71E+06 + + TH 7 | TH 1 TH 7 | TH 2 TH 7 | TH 3 TH 7 | TH 4 TH 7 | TH 5 TH 7 | TH 6 TH 7 | TH 7 + 6.34E+05 1.31E+03 -2.61E+04 -2.78E+04 -1.87E+03 4.88E+05 6.30E+06 + + TH 8 | TH 1 TH 8 | TH 2 TH 8 | TH 3 TH 8 | TH 4 TH 8 | TH 5 TH 8 | TH 6 TH 8 | TH 7 + -2.35E+04 -1.13E+02 5.89E+02 3.02E+02 1.71E+02 -1.84E+04 -2.13E+04 + + TH 8 | TH 8 TH10 | TH 1 TH10 | TH 2 TH10 | TH 3 TH10 | TH 4 TH10 | TH 5 TH10 | TH 6 + 1.72E+03 -7.80E+04 -5.79E+01 2.60E+03 -1.69E+02 3.74E+01 -5.99E+04 + + TH10 | TH 7 TH10 | TH 8 TH10 | TH10 TH11 | TH 1 TH11 | TH 2 TH11 | TH 3 TH11 | TH 4 + -7.65E+04 3.81E+02 3.29E+04 9.65E+03 -7.75E+00 -1.09E+02 -3.15E+01 + + TH11 | TH 5 TH11 | TH 6 TH11 | TH 7 TH11 | TH 8 TH11 | TH10 TH11 | TH11 TH13 | TH 1 + -5.02E+00 7.27E+03 1.16E+03 -5.09E+01 -1.68E+02 1.97E+01 1.33E+03 + + TH13 | TH 2 TH13 | TH 3 TH13 | TH 4 TH13 | TH 5 TH13 | TH 6 TH13 | TH 7 TH13 | TH 8 + 9.77E+00 -2.05E+02 -8.47E+01 -5.56E+00 1.15E+03 1.60E+03 -4.82E+01 + + TH13 | TH10 TH13 | TH11 TH13 | TH13 OM0101 | TH 1 OM0101 | TH 2 OM0101 | TH 3 OM0101 | TH 4 + 8.36E+00 3.56E+00 1.05E+02 4.73E+04 -1.61E+02 -1.52E+03 -5.56E+02 + + OM0101 | TH 5 OM0101 | TH 6 OM0101 | TH 7 OM0101 | TH 8 OM0101 | TH10 OM0101 | TH11 OM0101 | TH13 + -5.87E+01 3.61E+04 1.10E+02 -2.86E+02 -5.15E+02 9.52E+01 1.71E+01 + + OM0101 | OM0101 OM0202 | TH 1 OM0202 | TH 2 OM0202 | TH 3 OM0202 | TH 4 OM0202 | TH 5 OM0202 | TH 6 + 2.66E+03 5.86E+03 -8.28E+01 -3.42E+02 1.74E+02 -7.16E-01 2.58E+03 + + OM0202 | TH 7 OM0202 | TH 8 OM0202 | TH10 OM0202 | TH11 OM0202 | TH13 OM0202 | OM0101 OM0202 | OM0202 + -5.33E+03 -8.02E+01 2.81E+02 7.76E+00 4.52E+01 1.38E+03 4.40E+03 + + OM0303 | TH 1 OM0303 | TH 2 OM0303 | TH 3 OM0303 | TH 4 OM0303 | TH 5 OM0303 | TH 6 OM0303 | TH 7 + 4.15E+04 -2.94E+01 -3.88E+02 -1.30E+02 -1.22E+01 3.11E+04 4.52E+03 + + OM0303 | TH 8 OM0303 | TH10 OM0303 | TH11 OM0303 | TH13 OM0303 | OM0101 OM0303 | OM0202 OM0303 | OM0303 + -1.26E+02 -4.64E+02 8.48E+01 -3.01E+01 5.74E+02 3.17E+01 1.00E+03 + + OM0505 | TH 1 OM0505 | TH 2 OM0505 | TH 3 OM0505 | TH 4 OM0505 | TH 5 OM0505 | TH 6 OM0505 | TH 7 + 2.30E+04 2.39E+01 -1.16E+02 3.33E+02 1.16E+02 1.70E+04 -6.99E+03 + + OM0505 | TH 8 OM0505 | TH10 OM0505 | TH11 OM0505 | TH13 OM0505 | OM0101 OM0505 | OM0202 OM0505 | OM0303 + 1.11E+03 -2.88E+03 5.48E+01 -1.47E+02 -2.59E+02 -8.28E+02 6.99E+01 + + OM0505 | OM0505 OM0606 | TH 1 OM0606 | TH 2 OM0606 | TH 3 OM0606 | TH 4 OM0606 | TH 5 OM0606 | TH 6 + 6.82E+03 8.11E+03 1.02E+01 -4.55E+02 -3.36E+02 -5.92E+01 5.82E+03 + + OM0606 | TH 7 OM0606 | TH 8 OM0606 | TH10 OM0606 | TH11 OM0606 | TH13 OM0606 | OM0101 OM0606 | OM0202 + 9.57E+03 -3.61E+02 -9.29E+02 1.70E+01 -2.22E+01 1.45E+02 -4.52E+01 + + OM0606 | OM0303 OM0606 | OM0505 OM0606 | OM0606 OM0909 | TH 1 OM0909 | TH 2 OM0909 | TH 3 OM0909 | TH 4 + -5.24E+01 -3.18E+02 1.38E+03 -2.12E+04 2.04E+02 1.70E+02 3.91E+02 + + OM0909 | TH 5 OM0909 | TH 6 OM0909 | TH 7 OM0909 | TH 8 OM0909 | TH10 OM0909 | TH11 OM0909 | TH13 + -7.59E+01 -1.65E+04 -2.64E+02 -7.76E+02 2.01E+03 -3.66E+01 2.48E+01 + + OM0909 | OM0101 OM0909 | OM0202 OM0909 | OM0303 OM0909 | OM0505 OM0909 | OM0606 OM0909 | OM0909 OM1111 | TH 1 + -5.96E+02 8.64E+02 -7.77E+02 3.53E+03 2.23E+02 1.21E+04 -6.31E+03 + + OM1111 | TH 2 OM1111 | TH 3 OM1111 | TH 4 OM1111 | TH 5 OM1111 | TH 6 OM1111 | TH 7 OM1111 | TH 8 + -1.90E+01 6.90E+01 -1.32E+02 2.62E+01 -4.97E+03 1.84E+04 2.76E+02 + + OM1111 | TH10 OM1111 | TH11 OM1111 | TH13 OM1111 | OM0101 OM1111 | OM0202 OM1111 | OM0303 OM1111 | OM0505 + -5.63E+02 -1.34E+01 -6.20E+01 -1.51E+02 -2.70E+02 9.54E+01 1.49E+02 + + OM1111 | OM0606 OM1111 | OM0909 OM1111 | OM1111 SG0101 | TH 1 SG0101 | TH 2 SG0101 | TH 3 SG0101 | TH 4 + -1.02E+02 -2.00E+02 6.27E+02 1.93E+05 8.29E+01 9.26E+03 -3.26E+03 + + SG0101 | TH 5 SG0101 | TH 6 SG0101 | TH 7 SG0101 | TH 8 SG0101 | TH10 SG0101 | TH11 SG0101 | TH13 + 6.99E+02 1.35E+05 -6.14E+04 3.90E+03 -3.49E+04 3.70E+02 -1.18E+03 + + SG0101 | OM0101 SG0101 | OM0202 SG0101 | OM0303 SG0101 | OM0505 SG0101 | OM0606 SG0101 | OM0909 SG0101 | OM1111 + -1.30E+04 3.27E+03 -5.91E+03 1.08E+03 8.09E+03 1.20E+04 5.37E+02 + + SG0101 | SG0101 SG0303 | TH 1 SG0303 | TH 2 SG0303 | TH 3 SG0303 | TH 4 SG0303 | TH 5 SG0303 | TH 6 + 1.64E+06 -4.09E+05 2.25E+03 -4.77E+03 -1.67E+03 5.72E+02 -3.04E+05 + + SG0303 | TH 7 SG0303 | TH 8 SG0303 | TH10 SG0303 | TH11 SG0303 | TH13 SG0303 | OM0101 SG0303 | OM0202 + -4.47E+05 4.96E+03 2.46E+04 -7.04E+02 -2.80E+03 1.26E+04 -4.41E+03 + + SG0303 | OM0303 SG0303 | OM0505 SG0303 | OM0606 SG0303 | OM0909 SG0303 | OM1111 SG0303 | SG0101 SG0303 | SG0303 + 8.68E+03 2.27E+04 -1.44E+04 9.12E+03 1.18E+03 -1.06E+04 2.28E+06 + + SG0505 | TH 1 SG0505 | TH 2 SG0505 | TH 3 SG0505 | TH 4 SG0505 | TH 5 SG0505 | TH 6 SG0505 | TH 7 + -4.67E+05 -1.86E+03 -1.46E+04 -8.98E+03 -1.85E+01 -3.35E+05 5.83E+05 + + SG0505 | TH 8 SG0505 | TH10 SG0505 | TH11 SG0505 | TH13 SG0505 | OM0101 SG0505 | OM0202 SG0505 | OM0303 + 2.53E+03 1.01E+04 -1.02E+03 4.93E+03 2.09E+04 1.55E+04 -4.70E+03 + + SG0505 | OM0505 SG0505 | OM0606 SG0505 | OM0909 SG0505 | OM1111 SG0505 | SG0101 SG0505 | SG0303 SG0505 | SG0505 + -1.82E+04 -1.63E+04 -2.23E+04 2.60E+03 -2.39E+05 2.43E+05 1.73E+06 + + SG0606 | TH 1 SG0606 | TH 2 SG0606 | TH 3 SG0606 | TH 4 SG0606 | TH 5 SG0606 | TH 6 SG0606 | TH 7 + -4.46E+01 -3.56E-01 -1.79E+00 -1.48E+00 1.45E-01 -3.25E+01 1.19E+02 + + SG0606 | TH 8 SG0606 | TH10 SG0606 | TH11 SG0606 | TH13 SG0606 | OM0101 SG0606 | OM0202 SG0606 | OM0303 + 9.64E-01 6.20E+00 -1.15E-01 9.69E-01 4.56E+00 3.03E+00 -8.69E-01 + + SG0606 | OM0505 SG0606 | OM0606 SG0606 | OM0909 SG0606 | OM1111 SG0606 | SG0101 SG0606 | SG0303 SG0606 | SG0505 + -2.22E-02 -2.18E+00 3.02E+00 -4.36E-01 1.07E+01 4.09E+01 2.95E+02 + + SG0606 | SG0606 + 9.53E-02 +1 + + + + + + + + + + + + + + + + + + + + + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** EIGENVALUES OF COR MATRIX OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + 1 2 3 4 5 6 7 8 9 10 11 12 + 13 14 15 16 17 18 19 20 21 22 + + 3.33E-04 8.48E-02 1.10E-01 1.76E-01 2.12E-01 2.48E-01 2.97E-01 3.10E-01 3.85E-01 4.24E-01 5.06E-01 5.62E-01 + 7.06E-01 8.71E-01 9.85E-01 1.05E+00 1.25E+00 1.53E+00 1.80E+00 2.44E+00 3.60E+00 4.46E+00 + + Elapsed finaloutput time in seconds: 1.98 +1THERE ARE ERROR MESSAGES IN FILE PRDERR + #CPUT: Total CPU Time in Seconds, 740.094 +Stop Time: +Tue 04/09/2024 +03:26 PM diff --git a/vignette/models/evolocumab-tmdd-qss-pkpd-101/mrgsolve_code_evolocumab-tmdd.R b/vignette/models/evolocumab-tmdd-qss-pkpd-101/mrgsolve_code_evolocumab-tmdd.R new file mode 100644 index 0000000..a0a8146 --- /dev/null +++ b/vignette/models/evolocumab-tmdd-qss-pkpd-101/mrgsolve_code_evolocumab-tmdd.R @@ -0,0 +1,103 @@ +code <- ' +$PROB Simultaneous PKPD of the human anti-PCSK9 mAb evolocumab + +$PARAM + +HEALTHY=NA_real_ + +$THETA + +0.227505 2.71313 0.276166 2.11422 5.88232 0.265911 0.0528221 0.58245 0.72 0.304556 113.171 1 1.40841 + +$CMT + +DEPOT +TDA +TLC +CLDL + +$MAIN + +/* NOTE: There is no guarantee to the accuracy of the NONMEM to mrgsolve translator. It remains the responsibility of the user to validate the resulting mrgsolve code. */ + +/* NOTE: The nonmem2mrgsolve package remains in active development, please report bugs and feature requests to improve future versions. */ +/* NOTE: If you find nonmem2mrgsolve helpful, please consider giving it a star at github.com/Andy00000000000/nonmem2mrgsolve. */ + +/* NOTE: The translator does not currently convert T or TIME to SOLVERTIME. */ +/* NOTE: The translator does not currently convert MTIME() to self.mtime(). */ + +/* CALLFL=-2; */ +double TVKA = THETA1; +double KA = TVKA*exp(ETA(1)); +double TVV = THETA2; +double V = TVV*exp(ETA(2)); +double TVCL = THETA3; +double CL = TVCL*exp(ETA(3)); +double TVKDEG = THETA4; +double KDEG = TVKDEG*exp(ETA(4)); +double TVPCSK9_0 = THETA5*pow(THETA8,(HEALTHY)); +double PCSK9_0 = TVPCSK9_0*exp(ETA(5)); +double TVKSS = THETA6; +double KSS = TVKSS*exp(ETA(6)); +double TVKINT = THETA7; +double KINT = TVKINT*exp(ETA(7)); +double KEL = CL/V; +double KSYN = KDEG*PCSK9_0; +F_DEPOT=THETA9; +TLC_0=PCSK9_0; +double TVKOUT = THETA10; +double KOUT = TVKOUT*exp(ETA(8)); +double TVLDLC_0 = THETA11; +double LDLC_0 = TVLDLC_0*exp(ETA(9)); +double TVIMAX = THETA12; +double IMAX = TVIMAX*exp(ETA(10)); +double TVIC50 = THETA13; +double IC50 = TVIC50*exp(ETA(11)); +double INH0 = (IMAX*PCSK9_0)/(IC50+PCSK9_0); +double KIN = KOUT*(1.0-INH0)*LDLC_0; +CLDL_0=LDLC_0; + +$ODE + +double TDC=TDA/V; +double FDC=0.5*((TDC-TLC-KSS) + sqrt(pow((TDC-TLC-KSS),2.0 )+ 4.0*KSS*TDC)); +double FLC=TLC - (TDC - FDC); +dxdt_DEPOT=-KA*DEPOT; +dxdt_TDA=KA*DEPOT - KEL*FDC*V - (KINT*TLC*FDC*V)/(KSS+FDC); +dxdt_TLC=KSYN - KDEG*TLC - ((KINT-KDEG)*FDC*TLC)/(KSS+FDC); +double INH=(IMAX*PCSK9_0)/(IC50+PCSK9_0); +if(TIME>0){ +INH=(IMAX*FLC)/(IC50+FLC); +} +dxdt_CLDL=KIN - KOUT*(1.0-INH)*CLDL; + +$OMEGA @block + +0.0709136 +0 0.0402987 +0 0 0.11236 +0 0 0 0 +0 0 0 0 0.041995 +0 0 0 0 0 0.0869048 +0 0 0 0 0 0 0 +0 0 0 0 0 0 0 0 +0 0 0 0 0 0 0 0 0.0375891 +0 0 0 0 0 0 0 0 0 0 +0 0 0 0 0 0 0 0 0 0 0.127478 + +$CAPTURE + +KA +V +CL +KDEG +PCSK9_0 +KSS +KINT +KOUT +LDLC_0 +IMAX +IC50 +HEALTHY + +' \ No newline at end of file diff --git a/vignette/models/evolocumab-tmdd-qss-pkpd-101/mrgsolve_code_evolocumab-tmdd_user-modified.R b/vignette/models/evolocumab-tmdd-qss-pkpd-101/mrgsolve_code_evolocumab-tmdd_user-modified.R new file mode 100644 index 0000000..fe807c5 --- /dev/null +++ b/vignette/models/evolocumab-tmdd-qss-pkpd-101/mrgsolve_code_evolocumab-tmdd_user-modified.R @@ -0,0 +1,103 @@ +code <- ' +$PROB Simultaneous PKPD of the human anti-PCSK9 mAb evolocumab + +$PARAM + +HEALTHY=NA_real_ + +$THETA + +0.227505 2.71313 0.276166 2.11422 5.88232 0.265911 0.0528221 0.58245 0.72 0.304556 113.171 1 1.40841 + +$CMT + +DEPOT +TDA +TLC +CLDL + +$MAIN + +/* NOTE: There is no guarantee to the accuracy of the NONMEM to mrgsolve translator. It remains the responsibility of the user to validate the resulting mrgsolve code. */ + +/* NOTE: The nonmem2mrgsolve package remains in active development, please report bugs and feature requests to improve future versions. */ +/* NOTE: If you find nonmem2mrgsolve helpful, please consider giving it a star at github.com/Andy00000000000/nonmem2mrgsolve. */ + +/* NOTE: The translator does not currently convert T or TIME to SOLVERTIME. */ +/* NOTE: The translator does not currently convert MTIME() to self.mtime(). */ + +/* CALLFL=-2; */ +double TVKA = THETA1; +double KA = TVKA*exp(ETA(1)); +double TVV = THETA2; +double V = TVV*exp(ETA(2)); +double TVCL = THETA3; +double CL = TVCL*exp(ETA(3)); +double TVKDEG = THETA4; +double KDEG = TVKDEG*exp(ETA(4)); +double TVPCSK9_0 = THETA5*pow(THETA8,(HEALTHY)); +double PCSK9_0 = TVPCSK9_0*exp(ETA(5)); +double TVKSS = THETA6; +double KSS = TVKSS*exp(ETA(6)); +double TVKINT = THETA7; +double KINT = TVKINT*exp(ETA(7)); +double KEL = CL/V; +double KSYN = KDEG*PCSK9_0; +F_DEPOT=THETA9; +TLC_0=PCSK9_0; +double TVKOUT = THETA10; +double KOUT = TVKOUT*exp(ETA(8)); +double TVLDLC_0 = THETA11; +double LDLC_0 = TVLDLC_0*exp(ETA(9)); +double TVIMAX = THETA12; +double IMAX = TVIMAX*exp(ETA(10)); +double TVIC50 = THETA13; +double IC50 = TVIC50*exp(ETA(11)); +double INH0 = (IMAX*PCSK9_0)/(IC50+PCSK9_0); +double KIN = KOUT*(1.0-INH0)*LDLC_0; +CLDL_0=LDLC_0; + +$ODE + +double TDC=TDA/V; +double FDC=0.5*((TDC-TLC-KSS) + sqrt(pow((TDC-TLC-KSS),2.0 )+ 4.0*KSS*TDC)); +double FLC=TLC - (TDC - FDC); +dxdt_DEPOT=-KA*DEPOT; +dxdt_TDA=KA*DEPOT - KEL*FDC*V - (KINT*TLC*FDC*V)/(KSS+FDC); +dxdt_TLC=KSYN - KDEG*TLC - ((KINT-KDEG)*FDC*TLC)/(KSS+FDC); +double INH=(IMAX*PCSK9_0)/(IC50+PCSK9_0); +if(SOLVERTIME>0){ +INH=(IMAX*FLC)/(IC50+FLC); +} +dxdt_CLDL=KIN - KOUT*(1.0-INH)*CLDL; + +$OMEGA @block + +0.0709136 +0 0.0402987 +0 0 0.11236 +0 0 0 0 +0 0 0 0 0.041995 +0 0 0 0 0 0.0869048 +0 0 0 0 0 0 0 +0 0 0 0 0 0 0 0 +0 0 0 0 0 0 0 0 0.0375891 +0 0 0 0 0 0 0 0 0 0 +0 0 0 0 0 0 0 0 0 0 0.127478 + +$CAPTURE + +KA +V +CL +KDEG +PCSK9_0 +KSS +KINT +KOUT +LDLC_0 +IMAX +IC50 +HEALTHY + +' diff --git a/vignette/models/evolocumab-tmdd-qss-pkpd-101/run_nonmem2mrgsolve_evolocumab.R b/vignette/models/evolocumab-tmdd-qss-pkpd-101/run_nonmem2mrgsolve_evolocumab.R new file mode 100644 index 0000000..42904b7 --- /dev/null +++ b/vignette/models/evolocumab-tmdd-qss-pkpd-101/run_nonmem2mrgsolve_evolocumab.R @@ -0,0 +1,25 @@ +## Start #### + +# devtools::install_github("Andy00000000000/nonmem2mrgsolve") +# setwd("...") + +library("nonmem2mrgsolve") + +nonmem2mrgsolve( + "mod1.ctl", # filename + "./vignette/models/evolocumab-tmdd-qss-pkpd-101/", # dir + out.filename = "mrgsolve_code_evolocumab-tmdd" +) + +source("./vignette/models/evolocumab-tmdd-qss-pkpd-101/mrgsolve_code_evolocumab-tmdd.R") +mrgsolve::mcode("Test_Unmodified_Translation",code) + +source("./vignette/models/evolocumab-tmdd-qss-pkpd-101/mrgsolve_code_evolocumab-tmdd_user-modified.R") +mrgsolve::mcode("Test_Modified_Translation",code) + +# Shortcomings of the current translation which requires the user's attention: +# +# Line 69: This line needs to be manually changed by the user +# 1) Rename "TIME" to "SOLVERTIME" (since nonmem2mrgsolve does not currently translate reserved time-related variables) + +## End #### diff --git a/vignette/models/mavoglurant-pbpk-101/mod1.ctl b/vignette/models/mavoglurant-pbpk-101/mod1.ctl new file mode 100644 index 0000000..df7c57d --- /dev/null +++ b/vignette/models/mavoglurant-pbpk-101/mod1.ctl @@ -0,0 +1,157 @@ +$PROB Mavoglurant PBPK (Wendling et al., 2016. DOI: 10.1208/s12248-015-9840-7) presented as an nlmixr2 example (https://nlmixr2.org/articles/mavoglurant.html) + +$INPUT ID CMT EVID EVI2 MDV DV LNDV AMT TIME DOSE OCC RATE AGE SEX RACE WTKG HTM BLQ + +$DATA ../../data/Mavoglurant_A2121_nmpk_edited.csv + IGNORE=I + IGNORE=(OCC.GT.1) ; Match data subsets of nlmixr2 vignette + IGNORE=(ID.GE.812) ; Match data subsets of nlmixr2 vignette + IGNORE=(BLQ.EQ.1) ; Match data subsets of nlmixr2 vignette + +$SUBROUTINES ADVAN13 TRANS1 TOL=6 SUBROUTINES=D + +$MODEL + COMP=(LU) ; 01 + COMP=(HT) ; 02 + COMP=(BR) ; 03 + COMP=(MU) ; 04 + COMP=(AD) ; 05 + COMP=(SK) ; 06 + COMP=(SP) ; 07 + COMP=(PA) ; 08 + COMP=(LI) ; 09 + COMP=(ST) ; 10 + COMP=(GU) ; 11 + COMP=(BO) ; 12 + COMP=(KI) ; 13 + COMP=(AB) ; 14 + COMP=(VB,DEFDOSE,DEFOBS) ; 15 + COMP=(RB) ; 16 + +$PK + ;--- Initial + + CALLFL=-2 + R15=RATE + + ;--- Estimated Parameters + + lCLint = THETA(1) + MU_1 = lCLint + CLint = EXP(MU_1+ETA(1)) + + KbBR = EXP(THETA(2)) + KbMU = EXP(THETA(3)) + KbAD = EXP(THETA(4)) + KbBO = EXP(THETA(5)) + KbRB = EXP(THETA(6)) + + ;--- Fixed Physiological Parameters + + CO = (187.00*WTKG**0.81)*60.0/1000.0 ; Cardiac output (L/h) from White et al (1968) as presented by nlmixr2 vignette + QHT = 4.0 *CO/100.0 + QBR = 12.0*CO/100.0 + QMU = 17.0*CO/100.0 + QAD = 5.0 *CO/100.0 + QSK = 5.0 *CO/100.0 + QSP = 3.0 *CO/100.0 + QPA = 1.0 *CO/100.0 + QLI = 25.5*CO/100.0 + QST = 1.0 *CO/100.0 + QGU = 14.0*CO/100.0 + QHA = QLI - (QSP + QPA + QST + QGU) ; Hepatic artery blood flow + QBO = 5.0 *CO/100.0 + QKI = 19.0*CO/100.0 + QRB = CO - (QHT + QBR + QMU + QAD + QSK + QLI + QBO + QKI) + QLU = QHT + QBR + QMU + QAD + QSK + QLI + QBO + QKI + QRB + + VLU = (0.76 *WTKG/100.0)/1.051 + VHT = (0.47 *WTKG/100.0)/1.030 + VBR = (2.00 *WTKG/100.0)/1.036 + VMU = (40.00*WTKG/100.0)/1.041 + VAD = (21.42*WTKG/100.0)/0.916 + VSK = (3.71 *WTKG/100.0)/1.116 + VSP = (0.26 *WTKG/100.0)/1.054 + VPA = (0.14 *WTKG/100.0)/1.045 + VLI = (2.57 *WTKG/100.0)/1.040 + VST = (0.21 *WTKG/100.0)/1.050 + VGU = (1.44 *WTKG/100.0)/1.043 + VBO = (14.29*WTKG/100.0)/1.990 + VKI = (0.44 *WTKG/100.0)/1.050 + VAB = (2.81 *WTKG/100.0)/1.040 + VVB = (5.62 *WTKG/100.0)/1.040 + VRB = (3.86 *WTKG/100.0)/1.040 + + ;--- Fixed Drug-specific Parameters + + BP = 0.61 ; Blood:plasma partition coefficient + fup = 0.028 ; Fraction unbound in plasma + fub = fup/BP ; Fraction unbound in blood + + KbLU = exp(0.8334) + KbHT = exp(1.1205) + KbSK = exp(-.5238) + KbSP = exp(0.3224) + KbPA = exp(0.3224) + KbLI = exp(1.7604) + KbST = exp(0.3224) + KbGU = exp(1.2026) + KbKI = exp(1.3171) + + ;--- Finalize + + S15 = VVB*BP/1000.0 + +$DES + + DADT(1) = QLU*(A(15)/VVB - A(1)/KbLU/VLU) + DADT(2) = QHT*(A(14)/VAB - A(2)/KbHT/VHT) + DADT(3) = QBR*(A(14)/VAB - A(3)/KbBR/VBR) + DADT(4) = QMU*(A(14)/VAB - A(4)/KbMU/VMU) + DADT(5) = QAD*(A(14)/VAB - A(5)/KbAD/VAD) + DADT(6) = QSK*(A(14)/VAB - A(6)/KbSK/VSK) + DADT(7) = QSP*(A(14)/VAB - A(7)/KbSP/VSP) + DADT(8) = QPA*(A(14)/VAB - A(8)/KbPA/VPA) + DADT(9) = QHA*A(14)/VAB + QSP*A(7)/KbSP/VSP + QPA*A(8)/KbPA/VPA + QST*A(10)/KbST/VST + QGU*A(11)/KbGU/VGU - CLint*fub*A(9)/KbLI/VLI - QLI*A(9)/KbLI/VLI + DADT(10) = QST*(A(14)/VAB - A(10)/KbST/VST) + DADT(11) = QGU*(A(14)/VAB - A(11)/KbGU/VGU) + DADT(12) = QBO*(A(14)/VAB - A(12)/KbBO/VBO) + DADT(13) = QKI*(A(14)/VAB - A(13)/KbKI/VKI) + DADT(14) = QLU*(A(1)/KbLU/VLU - A(14)/VAB) + DADT(15) = QHT*A(2)/KbHT/VHT + QBR*A(3)/KbBR/VBR + QMU*A(4)/KbMU/VMU + QAD*A(5)/KbAD/VAD + QSK*A(6)/KbSK/VSK + QLI*A(9)/KbLI/VLI + QBO*A(12)/KbBO/VBO + QKI*A(13)/KbKI/VKI + QRB*A(16)/KbRB/VRB - QLU*A(15)/VVB + DADT(16) = QRB*(A(14)/VAB - A(16)/KbRB/VRB) + + C15 = A(15)/S15 + +$THETA + (7.6) ; lCLint + (1.1) ; lKbBR + (0.3) ; lKbMU + (2.0) ; lKbAD + (0.03) ; lKbBO + (0.3) ; lKbRB + +$OMEGA +(0, 4.00) ; IIV on CLint + +$SIGMA +10.0 ; proportional residual variability +1.00 ; additive residual variability + +$ERROR + + IPRED = A(15)/S15 + IRES=DV-IPRED + W=SQRT(IPRED**2*SIGMA(1,1)+SIGMA(2,2)) + IWRES=IRES/W + F_FLAG = 0 + Y = IPRED + IPRED*EPS(1) + EPS(2) + +; $EST METHOD=IMP INTERACTION NOABORT PRINT=5 NOABORT AUTO=1 RANMETHOD=S2P CTYPE=3 NITER=5000 + +$EST METHOD=CONDITIONAL INTERACTION MAXEVAL=9999 PRINT=1 NOABORT NOTBT NOOBT NOSBT NSIG=2 SIGL=6 + +$COV UNCONDITIONAL + +$TABLE ID EVID CMT DOSE C15 WTKG CLint +ETAS(1:LAST) NPDE CWRES IWRES IPRED NOPRINT ONEHEADER FILE=mod1.tbl diff --git a/vignette/models/mavoglurant-pbpk-101/mod1.ext b/vignette/models/mavoglurant-pbpk-101/mod1.ext new file mode 100644 index 0000000..f06cead --- /dev/null +++ b/vignette/models/mavoglurant-pbpk-101/mod1.ext @@ -0,0 +1,50 @@ +TABLE NO. 1: First Order Conditional Estimation with Interaction: Goal Function=MINIMUM VALUE OF OBJECTIVE FUNCTION: Problem=1 Subproblem=0 Superproblem1=0 Iteration1=0 Superproblem2=0 Iteration2=0 + ITERATION THETA1 THETA2 THETA3 THETA4 THETA5 THETA6 SIGMA(1,1) SIGMA(2,1) SIGMA(2,2) OMEGA(1,1) OBJ + 0 7.60000E+00 1.10000E+00 3.00000E-01 2.00000E+00 3.00000E-02 3.00000E-01 1.00000E+01 0.00000E+00 1.00000E+00 4.00000E+00 2653.2644430763830 + 1 7.89013E+00 1.10137E+00 3.01495E-01 2.30000E+00 3.00018E-02 3.00142E-01 9.98149E+00 0.00000E+00 1.00020E+00 3.99980E+00 2612.8117676464426 + 2 9.29882E+00 1.10891E+00 3.12021E-01 2.71431E+00 3.00151E-02 3.00935E-01 9.89852E+00 0.00000E+00 1.00056E+00 3.99823E+00 2610.6891245724055 + 3 9.99623E+00 1.11852E+00 3.26023E-01 2.64757E+00 3.00302E-02 3.01858E-01 9.82702E+00 0.00000E+00 1.00077E+00 3.99544E+00 2605.4042398419460 + 4 1.07531E+01 2.50465E+00 2.28216E+00 3.08980E+00 3.18054E-02 4.24569E-01 4.26380E+00 0.00000E+00 1.03328E+00 3.79118E+00 2449.9931245790508 + 5 1.07085E+01 2.88034E+00 2.32960E+00 3.10294E+00 3.20140E-02 4.43977E-01 3.98901E+00 0.00000E+00 1.03511E+00 3.77340E+00 2443.6624431420360 + 6 6.24820E+00 2.68308E+00 2.06195E+00 3.03630E+00 3.87756E-02 1.33154E+00 4.61359E-01 0.00000E+00 1.07419E+00 3.19667E+00 2251.0708960113002 + 7 5.16848E+00 2.61468E+00 1.97166E+00 3.01421E+00 3.89949E-02 1.15108E+00 2.81458E-01 0.00000E+00 1.07876E+00 2.97293E+00 2235.6318466860494 + 8 5.00628E+00 2.56818E+00 1.91237E+00 2.92750E+00 3.77349E-02 9.73981E-01 2.31417E-01 0.00000E+00 1.14378E+00 5.31227E+00 2230.0874857133399 + 9 3.67333E+00 1.87315E+00 1.04844E+00 2.36365E+00 -3.97876E-02 -1.14797E-01 1.12235E-01 0.00000E+00 1.57050E+01 2.95081E+01 2126.0836744033586 + 10 3.18873E+00 1.63318E+00 7.43131E-01 2.19035E+00 -9.79242E-02 -4.59189E-01 8.59558E-02 0.00000E+00 1.68340E+01 5.45015E+01 2103.0693180302328 + 11 2.79299E+00 1.42094E+00 5.64535E-01 2.20768E+00 3.43954E-01 -1.23265E+00 8.40926E-02 0.00000E+00 1.29816E+00 7.22370E+01 2090.6356567484536 + 12 2.56849E+00 1.55348E+00 5.12727E-01 2.34111E+00 1.53614E-02 -1.63254E+00 8.99406E-02 0.00000E+00 7.27995E-01 4.81787E+01 2077.9996500222251 + 13 2.19402E+00 1.63404E+00 4.78171E-01 2.35062E+00 -7.68071E-02 -2.02460E+00 8.73986E-02 0.00000E+00 5.84006E-01 4.02711E+01 2076.8272909493135 + 14 1.90144E+00 1.71144E+00 4.66011E-01 2.34519E+00 -1.74601E-01 -2.33307E+00 8.69276E-02 0.00000E+00 4.98768E-01 3.71769E+01 2076.6890024621471 + 15 1.90144E+00 1.71144E+00 4.66011E-01 2.34519E+00 -1.74601E-01 -2.33307E+00 8.69276E-02 0.00000E+00 4.98768E-01 3.71769E+01 2076.6890024621471 + 16 1.67166E+00 1.83982E+00 4.76686E-01 2.34859E+00 -2.11057E-01 -2.66352E+00 8.97223E-02 0.00000E+00 4.23895E-01 3.12381E+01 2075.5779670319403 + 17 6.68662E+00 2.03963E+00 5.19792E-01 2.31587E+00 -1.45267E-01 -3.76568E+00 8.74787E-02 0.00000E+00 3.96380E-01 3.07459E+01 2056.0535616458214 + 18 5.37270E+00 2.05013E+00 5.12593E-01 2.31138E+00 -1.52637E-01 -4.23874E+00 8.72086E-02 0.00000E+00 3.87315E-01 2.64261E+01 2055.2391901967908 + 19 4.66287E+00 2.01283E+00 4.96408E-01 2.31699E+00 -1.72502E-01 -4.41215E+00 8.74075E-02 0.00000E+00 3.85361E-01 2.35630E+01 2055.1517311728439 + 20 4.66287E+00 2.01283E+00 4.96408E-01 2.31699E+00 -1.72502E-01 -4.41215E+00 8.74075E-02 0.00000E+00 3.85361E-01 2.35630E+01 2055.1517311728439 + 21 4.47750E+00 2.02372E+00 4.96013E-01 2.31591E+00 -1.68251E-01 -4.47845E+00 8.71359E-02 0.00000E+00 3.82826E-01 2.17802E+01 2054.9745219033916 + 22 4.15993E+00 2.00215E+00 4.75654E-01 2.31688E+00 -1.72533E-01 -4.76637E+00 8.72142E-02 0.00000E+00 3.73513E-01 1.55120E+01 2053.0308694271475 + 23 5.15526E+00 2.00887E+00 4.08130E-01 2.31607E+00 -1.96340E-01 -6.37528E+00 8.45768E-02 0.00000E+00 3.28062E-01 2.28615E+00 2039.8660920503937 + 24 7.19656E+00 2.00854E+00 3.27511E-01 2.31709E+00 -2.28363E-01 -8.14078E+00 8.20936E-02 0.00000E+00 2.85462E-01 2.64558E-01 1974.9391433990561 + 25 7.04435E+00 2.03307E+00 3.74566E-01 2.29590E+00 -2.06079E-01 -8.03655E+00 8.66785E-02 0.00000E+00 2.98045E-01 2.94709E-01 1974.5444862388053 + 26 7.24171E+00 2.07334E+00 4.32217E-01 2.26396E+00 -1.76277E-01 -8.29979E+00 9.35533E-02 0.00000E+00 3.09373E-01 1.98773E-01 1970.0428535705735 + 27 7.14920E+00 2.06052E+00 4.89068E-01 2.35380E+00 -1.39656E-01 -8.44777E+00 8.37990E-02 0.00000E+00 3.56596E-01 1.54212E-01 1967.2574730390793 + 28 7.13728E+00 1.88636E+00 4.93083E-01 2.31983E+00 -1.87158E-01 -8.74898E+00 8.39644E-02 0.00000E+00 3.33434E-01 9.87576E-02 1964.4019324527226 + 29 7.15787E+00 1.98443E+00 4.54449E-01 2.32284E+00 -1.95231E-01 -8.90260E+00 8.87764E-02 0.00000E+00 3.22188E-01 7.97237E-02 1963.7772739376223 + 30 7.14485E+00 1.99059E+00 4.52406E-01 2.31644E+00 -1.96066E-01 -8.88831E+00 8.78743E-02 0.00000E+00 3.13133E-01 8.14532E-02 1963.7317217607010 + 31 7.14521E+00 1.99649E+00 4.51296E-01 2.30993E+00 -1.94667E-01 -8.88019E+00 8.65211E-02 0.00000E+00 3.00459E-01 8.27458E-02 1963.6787758263199 + 32 7.16067E+00 2.00054E+00 4.52002E-01 2.31015E+00 -1.85604E-01 -8.98750E+00 8.65005E-02 0.00000E+00 2.68010E-01 8.32930E-02 1963.6271921483342 + 33 7.16030E+00 2.00052E+00 4.52003E-01 2.31014E+00 -1.85919E-01 -9.02268E+00 8.65018E-02 0.00000E+00 2.68132E-01 8.32924E-02 1963.6271463019898 + 34 7.16030E+00 2.00052E+00 4.52003E-01 2.31014E+00 -1.85919E-01 -9.02268E+00 8.65018E-02 0.00000E+00 2.68132E-01 8.32924E-02 1963.6271463019898 + 35 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a/vignette/models/mavoglurant-pbpk-101/mod1.lst b/vignette/models/mavoglurant-pbpk-101/mod1.lst new file mode 100644 index 0000000..dca68b1 --- /dev/null +++ b/vignette/models/mavoglurant-pbpk-101/mod1.lst @@ -0,0 +1,958 @@ +Tue 04/09/2024 +01:34 PM +$PROBLEM Mavoglurant PBPK (Wendling et al.,2016. DOI: +; 10.1208/s12248-015-9840-7) presented as an nlmixr2 example +; (https://nlmixr2.org/articles/mavoglurant.html) +$INPUT ID CMT EVID EVI2 MDV DV LNDV AMT TIME DOSE OCC RATE AGE + SEX RACE WTKG HTM BLQ +$DATA Mavoglurant_A2121_nmpk_edited.csv IGNORE=I + IGNORE=(OCC.GT.1) IGNORE=(ID.GE.812) IGNORE=(BLQ.EQ.1) + ; Match data subsets of nlmixr2 vignette + ; Match data subsets of nlmixr2 vignette + ; Match data subsets of nlmixr2 vignette +$SUBROUTINE ADVAN13 TRANS1 TOL=6 SUBROUTINES=D +$MODEL COMP=(LU) ; 01 + COMP=(HT) ; 02 + COMP=(BR) ; 03 + COMP=(MU) ; 04 + COMP=(AD) ; 05 + COMP=(SK) ; 06 + COMP=(SP) ; 07 + COMP=(PA) ; 08 + COMP=(LI) ; 09 + COMP=(ST) ; 10 + COMP=(GU) ; 11 + COMP=(BO) ; 12 + COMP=(KI) ; 13 + COMP=(AB) ; 14 + COMP=(VB,DEFDOSE,DEFOBS) ; 15 + COMP=(RB) ; 16 +$PK + ;--- Initial + + CALLFL=-2 + R15=RATE + + ;--- Estimated Parameters + + lCLint = THETA(1) + MU_1 = lCLint + CLint = EXP(MU_1+ETA(1)) + + KbBR = EXP(THETA(2)) + KbMU = EXP(THETA(3)) + KbAD = EXP(THETA(4)) + KbBO = EXP(THETA(5)) + KbRB = EXP(THETA(6)) + + ;--- Fixed Physiological Parameters + + CO = (187.00*WTKG**0.81)*60.0/1000.0 ; Cardiac output (L/h) from White et al (1968) as presented by nlmixr2 vignette + QHT = 4.0 *CO/100.0 + QBR = 12.0*CO/100.0 + QMU = 17.0*CO/100.0 + QAD = 5.0 *CO/100.0 + QSK = 5.0 *CO/100.0 + QSP = 3.0 *CO/100.0 + QPA = 1.0 *CO/100.0 + QLI = 25.5*CO/100.0 + QST = 1.0 *CO/100.0 + QGU = 14.0*CO/100.0 + QHA = QLI - (QSP + QPA + QST + QGU) ; Hepatic artery blood flow + QBO = 5.0 *CO/100.0 + QKI = 19.0*CO/100.0 + QRB = CO - (QHT + QBR + QMU + QAD + QSK + QLI + QBO + QKI) + QLU = QHT + QBR + QMU + QAD + QSK + QLI + QBO + QKI + QRB + + VLU = (0.76 *WTKG/100.0)/1.051 + VHT = (0.47 *WTKG/100.0)/1.030 + VBR = (2.00 *WTKG/100.0)/1.036 + VMU = (40.00*WTKG/100.0)/1.041 + VAD = (21.42*WTKG/100.0)/0.916 + VSK = (3.71 *WTKG/100.0)/1.116 + VSP = (0.26 *WTKG/100.0)/1.054 + VPA = (0.14 *WTKG/100.0)/1.045 + VLI = (2.57 *WTKG/100.0)/1.040 + VST = (0.21 *WTKG/100.0)/1.050 + VGU = (1.44 *WTKG/100.0)/1.043 + VBO = (14.29*WTKG/100.0)/1.990 + VKI = (0.44 *WTKG/100.0)/1.050 + VAB = (2.81 *WTKG/100.0)/1.040 + VVB = (5.62 *WTKG/100.0)/1.040 + VRB = (3.86 *WTKG/100.0)/1.040 + + ;--- Fixed Drug-specific Parameters + + BP = 0.61 ; Blood:plasma partition coefficient + fup = 0.028 ; Fraction unbound in plasma + fub = fup/BP ; Fraction unbound in blood + + KbLU = exp(0.8334) + KbHT = exp(1.1205) + KbSK = exp(-.5238) + KbSP = exp(0.3224) + KbPA = exp(0.3224) + KbLI = exp(1.7604) + KbST = exp(0.3224) + KbGU = exp(1.2026) + KbKI = exp(1.3171) + + ;--- Finalize + + S15 = VVB*BP/1000.0 + +$DES + + DADT(1) = QLU*(A(15)/VVB - A(1)/KbLU/VLU) + DADT(2) = QHT*(A(14)/VAB - A(2)/KbHT/VHT) + DADT(3) = QBR*(A(14)/VAB - A(3)/KbBR/VBR) + DADT(4) = QMU*(A(14)/VAB - A(4)/KbMU/VMU) + DADT(5) = QAD*(A(14)/VAB - A(5)/KbAD/VAD) + DADT(6) = QSK*(A(14)/VAB - A(6)/KbSK/VSK) + DADT(7) = QSP*(A(14)/VAB - A(7)/KbSP/VSP) + DADT(8) = QPA*(A(14)/VAB - A(8)/KbPA/VPA) + DADT(9) = QHA*A(14)/VAB + QSP*A(7)/KbSP/VSP + QPA*A(8)/KbPA/VPA + QST*A(10)/KbST/VST + QGU*A(11)/KbGU/VGU - CLint*fub*A(9)/KbLI/VLI - QLI*A(9)/KbLI/VLI + DADT(10) = QST*(A(14)/VAB - A(10)/KbST/VST) + DADT(11) = QGU*(A(14)/VAB - A(11)/KbGU/VGU) + DADT(12) = QBO*(A(14)/VAB - A(12)/KbBO/VBO) + DADT(13) = QKI*(A(14)/VAB - A(13)/KbKI/VKI) + DADT(14) = QLU*(A(1)/KbLU/VLU - A(14)/VAB) + DADT(15) = QHT*A(2)/KbHT/VHT + QBR*A(3)/KbBR/VBR + QMU*A(4)/KbMU/VMU + QAD*A(5)/KbAD/VAD + QSK*A(6)/KbSK/VSK + QLI*A(9)/KbLI/VLI + QBO*A(12)/KbBO/VBO + QKI*A(13)/KbKI/VKI + QRB*A(16)/KbRB/VRB - QLU*A(15)/VVB + DADT(16) = QRB*(A(14)/VAB - A(16)/KbRB/VRB) + + C15 = A(15)/S15 + +$THETA 7.6 ; lCLint + 1.1 ; lKbBR + 0.3 ; lKbMU + 2.0 ; lKbAD + 0.03 ; lKbBO + 0.3 ; lKbRB +$OMEGA 4.00 ; IIV on CLint +$SIGMA 10.0 ; proportional residual variability + 1.00 ; additive residual variability +$ERROR + + IPRED = A(15)/S15 + IRES=DV-IPRED + W=SQRT(IPRED**2*SIGMA(1,1)+SIGMA(2,2)) + IWRES=IRES/W + F_FLAG = 0 + Y = IPRED + IPRED*EPS(1) + EPS(2) + +; $EST METHOD=IMP INTERACTION NOABORT PRINT=5 NOABORT AUTO=1 RANMETHOD=S2P CTYPE=3 NITER=5000 + +$ESTIMATION METHOD=CONDITIONAL INTERACTION MAXEVAL=9999 PRINT=1 + NOABORT NOTBT NOOBT NOSBT NSIG=2 SIGL=6 +$COVARIANCE UNCONDITIONAL +$TABLE ID EVID CMT DOSE C15 WTKG CLint ETAS(1:LAST) NPDE CWRES + IWRES IPRED NOPRINT ONEHEADER FILE=mod1.tbl + + +NM-TRAN MESSAGES + + WARNINGS AND ERRORS (IF ANY) FOR PROBLEM 1 + + (WARNING 2) NM-TRAN INFERS THAT THE DATA ARE POPULATION. + + (WARNING 48) DES-DEFINED ITEMS ARE COMPUTED ONLY WHEN EVENT TIME + INCREASES. E.G., DISPLAYED VALUES ASSOCIATED WITH THE FIRST EVENT RECORD + OF AN INDIVIDUAL RECORD ARE COMPUTED WITH (THE LAST ADVANCE TO) AN EVENT + TIME OF THE PRIOR INDIVIDUAL RECORD. + + (WARNING 79) SIGMA IS USED ON THE RIGHT. WITH A SUBSEQUENT RUN, IF AN + INITIAL ESTIMATE OF A DIAGONAL BLOCK OF SIGMA IS TO BE COMPUTED BY + NONMEM, THAT BLOCK WILL BE SET TO AN IDENTITY MATRIX DURING THAT + COMPUTATION. THIS COULD LEAD TO AN ARITHMETIC EXCEPTION.* + + * THE MAXIMUM NUMBER OF WARNINGS OF ONE OR MORE TYPES WAS REACHED. + IT IS POSSIBLE THAT SOME WARNING MESSAGES WERE SUPPRESSED. + +License Registered to: Enhanced Pharmacodynamics LLC +Expiration Date: 14 SEP 2024 +Current Date: 9 APR 2024 +Days until program expires : 155 +1NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM) VERSION 7.4.4 + ORIGINALLY DEVELOPED BY STUART BEAL, LEWIS SHEINER, AND ALISON BOECKMANN + CURRENT DEVELOPERS ARE ROBERT BAUER, ICON DEVELOPMENT SOLUTIONS, + AND ALISON BOECKMANN. IMPLEMENTATION, EFFICIENCY, AND STANDARDIZATION + PERFORMED BY NOUS INFOSYSTEMS. + + PROBLEM NO.: 1 + Mavoglurant PBPK (Wendling et al.,2016. DOI: +0DATA CHECKOUT RUN: NO + DATA SET LOCATED ON UNIT NO.: 2 + THIS UNIT TO BE REWOUND: NO + NO. OF DATA RECS IN DATA SET: 275 + NO. OF DATA ITEMS IN DATA SET: 18 + ID DATA ITEM IS DATA ITEM NO.: 1 + DEP VARIABLE IS DATA ITEM NO.: 6 + MDV DATA ITEM IS DATA ITEM NO.: 5 +0INDICES PASSED TO SUBROUTINE PRED: + 3 9 8 12 0 0 2 0 0 0 0 +0LABELS FOR DATA ITEMS: + ID CMT EVID EVI2 MDV DV LNDV AMT TIME DOSE OCC RATE AGE SEX RACE WTKG HTM BLQ +0(NONBLANK) LABELS FOR PRED-DEFINED ITEMS: + CLint C15 IPRED IWRES +0FORMAT FOR DATA: + (2(6E12.0/),6E12.0) + + TOT. NO. OF OBS RECS: 256 + TOT. NO. OF INDIVIDUALS: 19 +0LENGTH OF THETA: 6 +0DEFAULT THETA BOUNDARY TEST OMITTED: YES +0OMEGA HAS SIMPLE DIAGONAL FORM WITH DIMENSION: 1 +0DEFAULT OMEGA BOUNDARY TEST OMITTED: YES +0SIGMA HAS SIMPLE DIAGONAL FORM WITH DIMENSION: 2 +0DEFAULT SIGMA BOUNDARY TEST OMITTED: YES +0INITIAL ESTIMATE OF THETA: + 0.7600E+01 0.1100E+01 0.3000E+00 0.2000E+01 0.3000E-01 0.3000E+00 +0INITIAL ESTIMATE OF OMEGA: + 0.4000E+01 +0INITIAL ESTIMATE OF SIGMA: + 0.1000E+02 + 0.0000E+00 0.1000E+01 +0COVARIANCE STEP OMITTED: NO + EIGENVLS. PRINTED: NO + SPECIAL COMPUTATION: NO + COMPRESSED FORMAT: NO + GRADIENT METHOD USED: NOSLOW + SIGDIGITS ETAHAT (SIGLO): -1 + SIGDIGITS GRADIENTS (SIGL): -1 + EXCLUDE COV FOR FOCE (NOFCOV): NO + TURN OFF Cholesky Transposition of R Matrix (CHOLROFF): NO + KNUTHSUMOFF: -1 + RESUME COV ANALYSIS (RESUME): NO + SIR SAMPLE SIZE (SIRSAMPLE): -1 + NON-LINEARLY TRANSFORM THETAS DURING COV (THBND): 1 + PRECONDTIONING CYCLES (PRECOND): 0 + PRECONDTIONING TYPES (PRECONDS): TOS + FORCED PRECONDTIONING CYCLES (PFCOND):0 + PRECONDTIONING TYPE (PRETYPE): 0 + FORCED POS. DEFINITE SETTING: (FPOSDEF):0 +0TABLES STEP OMITTED: NO + NO. OF TABLES: 1 + SEED NUMBER (SEED): 11456 + RANMETHOD: 3U + MC SAMPLES (ESAMPLE): 300 + WRES SQUARE ROOT TYPE (WRESCHOL): EIGENVALUE +0-- TABLE 1 -- +0RECORDS ONLY: ALL +04 COLUMNS APPENDED: YES + PRINTED: NO + HEADER: YES + FILE TO BE FORWARDED: NO + FORMAT: S1PE11.4 + LFORMAT: + RFORMAT: + FIXED_EFFECT_ETAS: +0USER-CHOSEN ITEMS: + ID EVID CMT DOSE C15 WTKG CLint ETA1 NPDE CWRES IWRES IPRED +1DOUBLE PRECISION PREDPP VERSION 7.4.4 + + GENERAL NONLINEAR KINETICS MODEL WITH STIFF/NONSTIFF EQUATIONS (LSODA, ADVAN13) +0MODEL SUBROUTINE USER-SUPPLIED - ID NO. 9999 +0MAXIMUM NO. OF BASIC PK PARAMETERS: 48 +0COMPARTMENT ATTRIBUTES + COMPT. NO. FUNCTION INITIAL ON/OFF DOSE DEFAULT DEFAULT + STATUS ALLOWED ALLOWED FOR DOSE FOR OBS. + 1 LU ON YES YES NO NO + 2 HT ON YES YES NO NO + 3 BR ON YES YES NO NO + 4 MU ON YES YES NO NO + 5 AD ON YES YES NO NO + 6 SK ON YES YES NO NO + 7 SP ON YES YES NO NO + 8 PA ON YES YES NO NO + 9 LI ON YES YES NO NO + 10 ST ON YES YES NO NO + 11 GU ON YES YES NO NO + 12 BO ON YES YES NO NO + 13 KI ON YES YES NO NO + 14 AB ON YES YES NO NO + 15 VB ON YES YES YES YES + 16 RB ON YES YES NO NO + 17 OUTPUT OFF YES NO NO NO + INITIAL (BASE) TOLERANCE SETTINGS: + NRD (RELATIVE) VALUE(S) OF TOLERANCE: 6 + ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE: 12 +1 + ADDITIONAL PK PARAMETERS - ASSIGNMENT OF ROWS IN GG + COMPT. NO. INDICES + SCALE BIOAVAIL. ZERO-ORDER ZERO-ORDER ABSORB + FRACTION RATE DURATION LAG + 1 * * * * * + 2 * * * * * + 3 * * * * * + 4 * * * * * + 5 * * * * * + 6 * * * * * + 7 * * * * * + 8 * * * * * + 9 * * * * * + 10 * * * * * + 11 * * * * * + 12 * * * * * + 13 * * * * * + 14 * * * * * + 15 50 * 49 * * + 16 * * * * * + 17 * - - - - + - PARAMETER IS NOT ALLOWED FOR THIS MODEL + * PARAMETER IS NOT SUPPLIED BY PK SUBROUTINE; + WILL DEFAULT TO ONE IF APPLICABLE +0DATA ITEM INDICES USED BY PRED ARE: + EVENT ID DATA ITEM IS DATA ITEM NO.: 3 + TIME DATA ITEM IS DATA ITEM NO.: 9 + DOSE AMOUNT DATA ITEM IS DATA ITEM NO.: 8 + DOSE RATE DATA ITEM IS DATA ITEM NO.: 12 + COMPT. NO. DATA ITEM IS DATA ITEM NO.: 2 + +0PK SUBROUTINE CALLED WITH EVERY EVENT RECORD. + PK SUBROUTINE CALLED AT NONEVENT (ADDITIONAL AND LAGGED) DOSE TIMES. +0ERROR SUBROUTINE CALLED WITH EVERY EVENT RECORD. +0ERROR SUBROUTINE INDICATES THAT DERIVATIVES OF COMPARTMENT AMOUNTS ARE USED. +0DES SUBROUTINE USES COMPACT STORAGE MODE. +1 + + + #TBLN: 1 + #METH: First Order Conditional Estimation with Interaction + + ESTIMATION STEP OMITTED: NO + ANALYSIS TYPE: POPULATION + NUMBER OF SADDLE POINT RESET ITERATIONS: 0 + GRADIENT METHOD USED: NOSLOW + CONDITIONAL ESTIMATES USED: YES + CENTERED ETA: NO + EPS-ETA INTERACTION: YES + LAPLACIAN OBJ. FUNC.: NO + NO. OF FUNCT. EVALS. ALLOWED: 9999 + NO. OF SIG. FIGURES REQUIRED: 2 + INTERMEDIATE PRINTOUT: YES + ESTIMATE OUTPUT TO MSF: NO + ABORT WITH PRED EXIT CODE 1: NO + IND. OBJ. FUNC. VALUES SORTED: NO + NUMERICAL DERIVATIVE + FILE REQUEST (NUMDER): NONE + MAP (ETAHAT) ESTIMATION METHOD (OPTMAP): 0 + ETA HESSIAN EVALUATION METHOD (ETADER): 0 + INITIAL ETA FOR MAP ESTIMATION (MCETA): 0 + SIGDIGITS FOR MAP ESTIMATION (SIGLO): 6 + GRADIENT SIGDIGITS OF + FIXED EFFECTS PARAMETERS (SIGL): 6 + NOPRIOR SETTING (NOPRIOR): OFF + NOCOV SETTING (NOCOV): OFF + DERCONT SETTING (DERCONT): OFF + FINAL ETA RE-EVALUATION (FNLETA): ON + EXCLUDE NON-INFLUENTIAL (NON-INFL.) ETAS + IN SHRINKAGE (ETASTYPE): NO + NON-INFL. ETA CORRECTION (NONINFETA): OFF + RAW OUTPUT FILE (FILE): psn.ext + EXCLUDE TITLE (NOTITLE): NO + EXCLUDE COLUMN LABELS (NOLABEL): NO + FORMAT FOR ADDITIONAL FILES (FORMAT): S1PE12.5 + PARAMETER ORDER FOR OUTPUTS (ORDER): TSOL + WISHART PRIOR DF INTERPRETATION (WISHTYPE):0 + KNUTHSUMOFF: 0 + INCLUDE LNTWOPI: NO + INCLUDE CONSTANT TERM TO PRIOR (PRIORC): NO + INCLUDE CONSTANT TERM TO OMEGA (ETA) (OLNTWOPI):NO + ADDITIONAL CONVERGENCE TEST (CTYPE=4)?: NO + EM OR BAYESIAN METHOD USED: NONE + + TOLERANCES FOR ESTIMATION/EVALUATION STEP: + NRD (RELATIVE) VALUE(S) OF TOLERANCE: 6 + ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE: 12 + TOLERANCES FOR COVARIANCE STEP: + NRD (RELATIVE) VALUE(S) OF TOLERANCE: 6 + ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE: 12 + TOLERANCES FOR TABLE/SCATTER STEP: + NRD (RELATIVE) VALUE(S) OF TOLERANCE: 6 + ANRD (ABSOLUTE) VALUE(S) OF TOLERANCE: 12 + + THE FOLLOWING LABELS ARE EQUIVALENT + PRED=PREDI + RES=RESI + WRES=WRESI + IWRS=IWRESI + IPRD=IPREDI + IRS=IRESI + + MONITORING OF SEARCH: + + +0ITERATION NO.: 0 OBJECTIVE VALUE: 2653.26444307638 NO. OF FUNC. EVALS.: 10 + CUMULATIVE NO. OF FUNC. EVALS.: 10 + NPARAMETR: 7.6000E+00 1.1000E+00 3.0000E-01 2.0000E+00 3.0000E-02 3.0000E-01 4.0000E+00 1.0000E+01 1.0000E+00 + PARAMETER: 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 1.0000E-01 + GRADIENT: -9.7774E+02 -3.1881E+01 -1.2764E+02 -3.8418E+03 -1.5441E+00 -1.2123E+01 6.3171E+00 2.3732E+02 -2.6242E+01 + +0ITERATION NO.: 1 OBJECTIVE VALUE: 2612.81176764644 NO. OF FUNC. EVALS.: 12 + CUMULATIVE NO. OF FUNC. EVALS.: 22 + NPARAMETR: 7.8901E+00 1.1014E+00 3.0150E-01 2.3000E+00 3.0002E-02 3.0014E-01 3.9998E+00 9.9815E+00 1.0002E+00 + PARAMETER: 1.0382E-01 1.0012E-01 1.0050E-01 1.1500E-01 1.0001E-01 1.0005E-01 9.9975E-02 9.9073E-02 1.0010E-01 + GRADIENT: -9.2564E+02 -3.4233E+01 -1.7522E+02 -1.0345E+03 -2.2071E+00 -1.3199E+01 9.8211E+00 2.0840E+02 -8.9248E+00 + +0ITERATION NO.: 2 OBJECTIVE VALUE: 2610.68912457241 NO. OF FUNC. EVALS.: 14 + CUMULATIVE NO. OF FUNC. EVALS.: 36 + NPARAMETR: 9.2988E+00 1.1089E+00 3.1202E-01 2.7143E+00 3.0015E-02 3.0093E-01 3.9982E+00 9.8985E+00 1.0006E+00 + PARAMETER: 1.2235E-01 1.0081E-01 1.0401E-01 1.3572E-01 1.0005E-01 1.0031E-01 9.9779E-02 9.4900E-02 1.0028E-01 + GRADIENT: 1.0345E+02 -5.6712E+01 -3.1239E+02 1.6556E+03 -2.9898E+00 -1.8552E+01 2.7342E+01 1.5333E+02 -5.3829E-01 + +0ITERATION NO.: 3 OBJECTIVE VALUE: 2605.40423984195 NO. OF FUNC. EVALS.: 13 + CUMULATIVE NO. OF FUNC. EVALS.: 49 + NPARAMETR: 9.9962E+00 1.1185E+00 3.2602E-01 2.6476E+00 3.0030E-02 3.0186E-01 3.9954E+00 9.8270E+00 1.0008E+00 + PARAMETER: 1.3153E-01 1.0168E-01 1.0867E-01 1.3238E-01 1.0010E-01 1.0062E-01 9.9430E-02 9.1275E-02 1.0038E-01 + GRADIENT: 4.5938E+02 -5.9832E+01 -3.2219E+02 1.4663E+03 -2.7546E+00 -1.8613E+01 2.0947E+01 1.3590E+02 -1.4852E+00 + +0ITERATION NO.: 4 OBJECTIVE VALUE: 2449.99312457905 NO. OF FUNC. EVALS.: 11 + CUMULATIVE NO. OF FUNC. EVALS.: 60 + NPARAMETR: 1.0753E+01 2.5046E+00 2.2822E+00 3.0898E+00 3.1805E-02 4.2457E-01 3.7912E+00 4.2638E+00 1.0333E+00 + PARAMETER: 1.4149E-01 2.2770E-01 7.6072E-01 1.5449E-01 1.0602E-01 1.4152E-01 7.3192E-02 -3.2621E-01 1.1637E-01 + GRADIENT: 9.7184E+02 -3.7685E+02 2.8799E+02 9.0455E+01 -4.2423E+00 -5.5988E+01 -3.2151E-01 5.9477E+01 7.8690E-01 + +0ITERATION NO.: 5 OBJECTIVE VALUE: 2443.66244314204 NO. OF FUNC. EVALS.: 12 + CUMULATIVE NO. OF FUNC. EVALS.: 72 + NPARAMETR: 1.0709E+01 2.8803E+00 2.3296E+00 3.1029E+00 3.2014E-02 4.4398E-01 3.7734E+00 3.9890E+00 1.0351E+00 + PARAMETER: 1.4090E-01 2.6185E-01 7.7653E-01 1.5515E-01 1.0671E-01 1.4799E-01 7.0841E-02 -3.5952E-01 1.1725E-01 + GRADIENT: 1.0419E+03 -4.3251E+01 2.4796E+02 3.8950E+01 -3.1436E+00 -5.8433E+01 -1.7164E+00 5.3046E+01 9.2924E-01 + +0ITERATION NO.: 6 OBJECTIVE VALUE: 2251.07089601130 NO. OF FUNC. EVALS.: 11 + CUMULATIVE NO. OF FUNC. EVALS.: 83 + NPARAMETR: 6.2482E+00 2.6831E+00 2.0619E+00 3.0363E+00 3.8776E-02 1.3315E+00 3.1967E+00 4.6136E-01 1.0742E+00 + PARAMETER: 8.2213E-02 2.4392E-01 6.8732E-01 1.5181E-01 1.2925E-01 4.4385E-01 -1.2093E-02 -1.4381E+00 1.3578E-01 + GRADIENT: -6.7107E+02 5.4343E+02 1.9583E+02 -6.0719E+02 2.8823E+00 6.5493E+01 2.4064E+01 1.1132E+02 1.8367E+00 + +0ITERATION NO.: 7 OBJECTIVE VALUE: 2235.63184668605 NO. OF FUNC. EVALS.: 11 + CUMULATIVE NO. OF FUNC. EVALS.: 94 + NPARAMETR: 5.1685E+00 2.6147E+00 1.9717E+00 3.0142E+00 3.8995E-02 1.1511E+00 2.9729E+00 2.8146E-01 1.0788E+00 + PARAMETER: 6.8006E-02 2.3770E-01 6.5722E-01 1.5071E-01 1.2998E-01 3.8369E-01 -4.8372E-02 -1.6852E+00 1.3791E-01 + GRADIENT: -1.5563E+03 7.1021E+02 2.3626E+02 -8.3364E+02 4.9444E+00 7.1148E+01 -6.2199E+00 3.1841E+01 1.5134E+00 + +0ITERATION NO.: 8 OBJECTIVE VALUE: 2230.08748571334 NO. OF FUNC. EVALS.: 11 + CUMULATIVE NO. OF FUNC. EVALS.: 105 + NPARAMETR: 5.0063E+00 2.5682E+00 1.9124E+00 2.9275E+00 3.7735E-02 9.7398E-01 5.3123E+00 2.3142E-01 1.1438E+00 + PARAMETER: 6.5872E-02 2.3347E-01 6.3746E-01 1.4637E-01 1.2578E-01 3.2466E-01 2.4186E-01 -1.7831E+00 1.6717E-01 + GRADIENT: -8.7691E+02 7.7632E+02 3.1526E+02 -8.4979E+02 5.4767E+00 5.4145E+01 8.9162E+00 -2.4133E+01 1.5129E+00 + +0ITERATION NO.: 9 OBJECTIVE VALUE: 2126.08367440336 NO. OF FUNC. EVALS.: 13 + CUMULATIVE NO. OF FUNC. EVALS.: 118 + NPARAMETR: 3.6733E+00 1.8731E+00 1.0484E+00 2.3636E+00 -3.9788E-02 -1.1480E-01 2.9508E+01 1.1223E-01 1.5705E+01 + PARAMETER: 4.8333E-02 1.7029E-01 3.4948E-01 1.1818E-01 -1.3263E-01 -3.8266E-02 1.0992E+00 -2.1449E+00 1.4770E+00 + GRADIENT: 6.1584E+01 1.4218E+02 4.6649E+02 -6.0966E+02 5.8285E+00 -2.9366E+01 2.1279E+01 8.0255E+00 3.0112E+01 + +0ITERATION NO.: 10 OBJECTIVE VALUE: 2103.06931803023 NO. OF FUNC. EVALS.: 11 + CUMULATIVE NO. OF FUNC. EVALS.: 129 + NPARAMETR: 3.1887E+00 1.6332E+00 7.4313E-01 2.1904E+00 -9.7924E-02 -4.5919E-01 5.4502E+01 8.5956E-02 1.6834E+01 + PARAMETER: 4.1957E-02 1.4847E-01 2.4771E-01 1.0952E-01 -3.2641E-01 -1.5306E-01 1.4060E+00 -2.2783E+00 1.5117E+00 + GRADIENT: 3.2970E+02 -8.4189E+01 2.7942E+02 -4.2319E+02 2.5641E+00 -2.3584E+01 2.6291E+01 2.7502E+00 3.3145E+01 + +0ITERATION NO.: 11 OBJECTIVE VALUE: 2090.63565674845 NO. OF FUNC. EVALS.: 11 + CUMULATIVE NO. OF FUNC. EVALS.: 140 + NPARAMETR: 2.7930E+00 1.4209E+00 5.6454E-01 2.2077E+00 3.4395E-01 -1.2327E+00 7.2237E+01 8.4093E-02 1.2982E+00 + PARAMETER: 3.6750E-02 1.2918E-01 1.8818E-01 1.1038E-01 1.1465E+00 -4.1088E-01 1.5468E+00 -2.2892E+00 2.3047E-01 + GRADIENT: 7.3240E+02 -1.8959E+02 1.7060E+02 -9.9700E+02 4.5198E+00 -3.3894E+00 2.7736E+01 -2.4638E+01 -4.2288E-01 + +0ITERATION NO.: 12 OBJECTIVE VALUE: 2077.99965002223 NO. OF FUNC. EVALS.: 11 + CUMULATIVE NO. OF FUNC. EVALS.: 151 + NPARAMETR: 2.5685E+00 1.5535E+00 5.1273E-01 2.3411E+00 1.5361E-02 -1.6325E+00 4.8179E+01 8.9941E-02 7.2799E-01 + PARAMETER: 3.3796E-02 1.4123E-01 1.7091E-01 1.1706E-01 5.1205E-02 -5.4418E-01 1.3443E+00 -2.2556E+00 -5.8731E-02 + GRADIENT: 6.7137E+02 -1.9942E+02 -1.9420E+01 2.8992E+02 -3.4960E-01 1.2314E+00 2.1230E+01 1.4906E+01 1.7407E+00 + +0ITERATION NO.: 13 OBJECTIVE VALUE: 2076.82729094931 NO. OF FUNC. EVALS.: 11 + CUMULATIVE NO. OF FUNC. EVALS.: 162 + NPARAMETR: 2.1940E+00 1.6340E+00 4.7817E-01 2.3506E+00 -7.6807E-02 -2.0246E+00 4.0271E+01 8.7399E-02 5.8401E-01 + PARAMETER: 2.8869E-02 1.4855E-01 1.5939E-01 1.1753E-01 -2.5602E-01 -6.7487E-01 1.2547E+00 -2.2699E+00 -1.6892E-01 + GRADIENT: 6.4939E+02 -1.9892E+02 -6.2892E+01 4.8911E+02 -7.1646E-01 2.4566E+00 1.4662E+01 5.9836E+00 1.1985E+00 + +0ITERATION NO.: 14 OBJECTIVE VALUE: 2076.68900246215 NO. OF FUNC. EVALS.: 11 + CUMULATIVE NO. OF FUNC. EVALS.: 173 + NPARAMETR: 1.9014E+00 1.7114E+00 4.6601E-01 2.3452E+00 -1.7460E-01 -2.3331E+00 3.7177E+01 8.6928E-02 4.9877E-01 + PARAMETER: 2.5019E-02 1.5559E-01 1.5534E-01 1.1726E-01 -5.8200E-01 -7.7769E-01 1.2147E+00 -2.2726E+00 -2.4781E-01 + GRADIENT: 6.0628E+02 -1.8765E+02 -7.2981E+01 4.6906E+02 -1.3099E+00 2.4200E+00 9.6864E+00 5.1476E+00 8.3548E-01 + +0ITERATION NO.: 15 OBJECTIVE VALUE: 2076.68900246215 NO. OF FUNC. EVALS.: 28 + CUMULATIVE NO. OF FUNC. EVALS.: 201 + NPARAMETR: 1.9014E+00 1.7114E+00 4.6601E-01 2.3452E+00 -1.7460E-01 -2.3331E+00 3.7177E+01 8.6928E-02 4.9877E-01 + PARAMETER: 2.5019E-02 1.5559E-01 1.5534E-01 1.1726E-01 -5.8200E-01 -7.7769E-01 1.2147E+00 -2.2726E+00 -2.4781E-01 + GRADIENT: 1.2944E+02 -1.8845E+02 -7.4019E+01 4.5007E+02 -1.4817E+00 2.3649E+00 9.6864E+00 3.8903E+00 8.3476E-01 + +0ITERATION NO.: 16 OBJECTIVE VALUE: 2075.57796703194 NO. OF FUNC. EVALS.: 25 + CUMULATIVE NO. OF FUNC. EVALS.: 226 + NPARAMETR: 1.6717E+00 1.8398E+00 4.7669E-01 2.3486E+00 -2.1106E-01 -2.6635E+00 3.1238E+01 8.9722E-02 4.2390E-01 + PARAMETER: 2.1995E-02 1.6726E-01 1.5890E-01 1.1743E-01 -7.0352E-01 -8.8784E-01 1.1277E+00 -2.2568E+00 -3.2913E-01 + GRADIENT: 2.8005E+01 -1.2414E+02 -4.8543E+01 3.5857E+02 -1.0375E+00 2.0525E+00 1.2215E+00 1.5017E+01 8.1333E-01 + +0ITERATION NO.: 17 OBJECTIVE VALUE: 2056.05356164582 NO. OF FUNC. EVALS.: 36 + CUMULATIVE NO. OF FUNC. EVALS.: 262 RESET HESSIAN, TYPE I + NPARAMETR: 6.6866E+00 2.0396E+00 5.1979E-01 2.3159E+00 -1.4527E-01 -3.7657E+00 3.0746E+01 8.7479E-02 3.9638E-01 + PARAMETER: 8.7982E-02 1.8542E-01 1.7326E-01 1.1579E-01 -4.8422E-01 -1.2552E+00 1.1197E+00 -2.2695E+00 -3.6269E-01 + GRADIENT: 9.5292E+02 1.0143E+02 7.4048E+01 -1.6854E+02 1.4310E+00 8.6338E-01 3.7570E+01 -6.3253E+00 1.0593E-01 + +0ITERATION NO.: 18 OBJECTIVE VALUE: 2055.23919019679 NO. OF FUNC. EVALS.: 11 + CUMULATIVE NO. OF FUNC. EVALS.: 273 + NPARAMETR: 5.3727E+00 2.0501E+00 5.1259E-01 2.3114E+00 -1.5264E-01 -4.2387E+00 2.6426E+01 8.7209E-02 3.8732E-01 + PARAMETER: 7.0693E-02 1.8638E-01 1.7086E-01 1.1557E-01 -5.0879E-01 -1.4129E+00 1.0440E+00 -2.2710E+00 -3.7426E-01 + GRADIENT: 8.0313E+02 1.0606E+02 7.2545E+01 -2.0134E+02 1.3960E+00 5.7063E-01 3.3166E+01 -6.6705E+00 1.2881E-02 + +0ITERATION NO.: 19 OBJECTIVE VALUE: 2055.15173117284 NO. OF FUNC. EVALS.: 11 + CUMULATIVE NO. OF FUNC. EVALS.: 284 + NPARAMETR: 4.6629E+00 2.0128E+00 4.9641E-01 2.3170E+00 -1.7250E-01 -4.4121E+00 2.3563E+01 8.7408E-02 3.8536E-01 + PARAMETER: 6.1354E-02 1.8298E-01 1.6547E-01 1.1585E-01 -5.7501E-01 -1.4707E+00 9.8669E-01 -2.2699E+00 -3.7679E-01 + GRADIENT: 6.9056E+02 4.5389E+01 3.8800E+01 -7.6284E+01 6.8400E-01 4.5457E-01 2.7675E+01 -1.0736E+00 1.1506E-01 + +0ITERATION NO.: 20 OBJECTIVE VALUE: 2055.15173117284 NO. OF FUNC. EVALS.: 27 + CUMULATIVE NO. OF FUNC. EVALS.: 311 + NPARAMETR: 4.6629E+00 2.0128E+00 4.9641E-01 2.3170E+00 -1.7250E-01 -4.4121E+00 2.3563E+01 8.7408E-02 3.8536E-01 + PARAMETER: 6.1354E-02 1.8298E-01 1.6547E-01 1.1585E-01 -5.7501E-01 -1.4707E+00 9.8669E-01 -2.2699E+00 -3.7679E-01 + GRADIENT: 2.2371E+02 4.3806E+01 3.7898E+01 -9.5590E+01 5.1853E-01 4.0174E-01 2.7675E+01 -2.3545E+00 1.1409E-01 + +0ITERATION NO.: 21 OBJECTIVE VALUE: 2054.97452190339 NO. OF FUNC. EVALS.: 24 + CUMULATIVE NO. OF FUNC. EVALS.: 335 + NPARAMETR: 4.4775E+00 2.0237E+00 4.9601E-01 2.3159E+00 -1.6825E-01 -4.4785E+00 2.1780E+01 8.7136E-02 3.8283E-01 + PARAMETER: 5.8914E-02 1.8397E-01 1.6534E-01 1.1580E-01 -5.6084E-01 -1.4928E+00 9.4735E-01 -2.2714E+00 -3.8009E-01 + GRADIENT: 1.8204E+02 5.5926E+01 4.2474E+01 -1.1397E+02 6.2410E-01 3.7399E-01 2.5147E+01 -4.1176E+00 8.0202E-02 + +0ITERATION NO.: 22 OBJECTIVE VALUE: 2053.03086942715 NO. OF FUNC. EVALS.: 25 + CUMULATIVE NO. OF FUNC. EVALS.: 360 + NPARAMETR: 4.1599E+00 2.0022E+00 4.7565E-01 2.3169E+00 -1.7253E-01 -4.7664E+00 1.5512E+01 8.7214E-02 3.7351E-01 + PARAMETER: 5.4736E-02 1.8201E-01 1.5855E-01 1.1584E-01 -5.7511E-01 -1.5888E+00 7.7766E-01 -2.2710E+00 -3.9240E-01 + GRADIENT: -9.7006E+00 1.4504E+01 1.4990E+01 -3.5317E+01 2.1940E-01 2.8360E-01 1.5584E+01 -3.8010E-02 1.0061E-01 + +0ITERATION NO.: 23 OBJECTIVE VALUE: 2039.86609205039 NO. OF FUNC. EVALS.: 26 + CUMULATIVE NO. OF FUNC. EVALS.: 386 + NPARAMETR: 5.1553E+00 2.0089E+00 4.0813E-01 2.3161E+00 -1.9634E-01 -6.3753E+00 2.2861E+00 8.4577E-02 3.2806E-01 + PARAMETER: 6.7832E-02 1.8262E-01 1.3604E-01 1.1580E-01 -6.5447E-01 -2.1251E+00 -1.7971E-01 -2.2863E+00 -4.5728E-01 + GRADIENT: -1.9191E+03 -3.9449E+01 -3.5874E+01 9.3585E+01 -4.9597E-01 6.0463E-02 -2.9598E+01 -3.4354E+00 1.5274E-02 + +0ITERATION NO.: 24 OBJECTIVE VALUE: 1974.93914339906 NO. OF FUNC. EVALS.: 25 + CUMULATIVE NO. OF FUNC. EVALS.: 411 + NPARAMETR: 7.1966E+00 2.0085E+00 3.2751E-01 2.3171E+00 -2.2836E-01 -8.1408E+00 2.6456E-01 8.2094E-02 2.8546E-01 + PARAMETER: 9.4692E-02 1.8259E-01 1.0917E-01 1.1585E-01 -7.6121E-01 -2.7136E+00 -1.2580E+00 -2.3012E+00 -5.2682E-01 + GRADIENT: 1.2762E+03 -1.4302E+02 -1.2690E+02 5.5002E+02 -1.6931E+00 8.7794E-03 2.3988E+01 -1.8866E+01 -3.6388E-01 + +0ITERATION NO.: 25 OBJECTIVE VALUE: 1974.54448623881 NO. OF FUNC. EVALS.: 24 + CUMULATIVE NO. OF FUNC. EVALS.: 435 + NPARAMETR: 7.0444E+00 2.0331E+00 3.7457E-01 2.2959E+00 -2.0608E-01 -8.0366E+00 2.9471E-01 8.6678E-02 2.9804E-01 + PARAMETER: 9.2689E-02 1.8482E-01 1.2486E-01 1.1479E-01 -6.8693E-01 -2.6789E+00 -1.2040E+00 -2.2741E+00 -5.0526E-01 + GRADIENT: -4.4202E+02 -5.9766E+01 -5.8633E+01 2.4605E+01 -7.9530E-01 8.2294E-03 2.4170E+01 6.5936E+00 -2.8197E-01 + +0ITERATION NO.: 26 OBJECTIVE VALUE: 1970.04285357057 NO. OF FUNC. EVALS.: 26 + CUMULATIVE NO. OF FUNC. EVALS.: 461 + NPARAMETR: 7.2417E+00 2.0733E+00 4.3222E-01 2.2640E+00 -1.7628E-01 -8.2998E+00 1.9877E-01 9.3553E-02 3.0937E-01 + PARAMETER: 9.5286E-02 1.8849E-01 1.4407E-01 1.1320E-01 -5.8759E-01 -2.7666E+00 -1.4009E+00 -2.2359E+00 -4.8660E-01 + GRADIENT: 1.4494E+03 2.8530E+01 2.8734E+00 -4.7785E+02 1.0626E-01 8.3064E-03 1.9146E+01 2.7714E+01 -7.0151E-01 + +0ITERATION NO.: 27 OBJECTIVE VALUE: 1967.25747303908 NO. OF FUNC. EVALS.: 24 + CUMULATIVE NO. OF FUNC. EVALS.: 485 + NPARAMETR: 7.1492E+00 2.0605E+00 4.8907E-01 2.3538E+00 -1.3966E-01 -8.4478E+00 1.5421E-01 8.3799E-02 3.5660E-01 + PARAMETER: 9.4068E-02 1.8732E-01 1.6302E-01 1.1769E-01 -4.6552E-01 -2.8159E+00 -1.5279E+00 -2.2910E+00 -4.1558E-01 + GRADIENT: 3.5121E+02 9.7610E+01 4.2680E+01 2.7802E+02 1.0564E+00 8.2139E-03 1.5016E+01 -2.2576E+01 5.6381E-01 + +0ITERATION NO.: 28 OBJECTIVE VALUE: 1964.40193245272 NO. OF FUNC. EVALS.: 24 + CUMULATIVE NO. OF FUNC. EVALS.: 509 + NPARAMETR: 7.1373E+00 1.8864E+00 4.9308E-01 2.3198E+00 -1.8716E-01 -8.7490E+00 9.8758E-02 8.3964E-02 3.3343E-01 + PARAMETER: 9.3912E-02 1.7149E-01 1.6436E-01 1.1599E-01 -6.2386E-01 -2.9163E+00 -1.7507E+00 -2.2900E+00 -4.4916E-01 + GRADIENT: -3.8056E+01 -4.9492E+01 1.5491E+01 2.8659E+01 -1.0772E-01 5.2496E-03 4.7636E+00 -1.2848E+01 1.8394E-01 + +0ITERATION NO.: 29 OBJECTIVE VALUE: 1963.77727393762 NO. OF FUNC. EVALS.: 24 + CUMULATIVE NO. OF FUNC. EVALS.: 533 + NPARAMETR: 7.1579E+00 1.9844E+00 4.5445E-01 2.3228E+00 -1.9523E-01 -8.9026E+00 7.9724E-02 8.8776E-02 3.2219E-01 + PARAMETER: 9.4183E-02 1.8040E-01 1.5148E-01 1.1614E-01 -6.5077E-01 -2.9675E+00 -1.8577E+00 -2.2621E+00 -4.6631E-01 + GRADIENT: 4.8596E+02 -2.0213E+01 -1.2959E+01 1.5018E+02 -2.0411E-01 4.7835E-03 -1.3068E+00 1.0028E+01 4.7151E-01 + +0ITERATION NO.: 30 OBJECTIVE VALUE: 1963.73172176070 NO. OF FUNC. EVALS.: 24 + CUMULATIVE NO. OF FUNC. EVALS.: 557 + NPARAMETR: 7.1449E+00 1.9906E+00 4.5241E-01 2.3164E+00 -1.9607E-01 -8.8883E+00 8.1453E-02 8.7874E-02 3.1313E-01 + PARAMETER: 9.4011E-02 1.8096E-01 1.5080E-01 1.1582E-01 -6.5355E-01 -2.9628E+00 -1.8470E+00 -2.2672E+00 -4.8056E-01 + GRADIENT: 8.9267E+01 -1.2004E+01 -6.5506E+00 6.8832E+01 -1.2857E-01 3.4714E-03 -6.6732E-01 6.7561E+00 3.3146E-01 + +0ITERATION NO.: 31 OBJECTIVE VALUE: 1963.67877582632 NO. OF FUNC. EVALS.: 24 + CUMULATIVE NO. OF FUNC. EVALS.: 581 + NPARAMETR: 7.1452E+00 1.9965E+00 4.5130E-01 2.3099E+00 -1.9467E-01 -8.8802E+00 8.2746E-02 8.6521E-02 3.0046E-01 + PARAMETER: 9.4016E-02 1.8150E-01 1.5043E-01 1.1550E-01 -6.4889E-01 -2.9601E+00 -1.8391E+00 -2.2750E+00 -5.0122E-01 + GRADIENT: 1.1589E+02 -3.3305E+00 -7.1896E-01 -2.7353E+00 -4.9492E-02 3.4053E-03 -1.9565E-01 1.0391E-01 1.0998E-01 + +0ITERATION NO.: 32 OBJECTIVE VALUE: 1963.62719214833 NO. OF FUNC. EVALS.: 33 + CUMULATIVE NO. OF FUNC. EVALS.: 614 RESET HESSIAN, TYPE I + NPARAMETR: 7.1607E+00 2.0005E+00 4.5200E-01 2.3102E+00 -1.8560E-01 -8.9875E+00 8.3293E-02 8.6501E-02 2.6801E-01 + PARAMETER: 9.4219E-02 1.8187E-01 1.5067E-01 1.1551E-01 -6.1868E-01 -2.9958E+00 -1.8358E+00 -2.2751E+00 -5.5836E-01 + GRADIENT: 1.0732E+03 1.5270E+00 -2.1702E-02 1.4430E+01 1.2292E-01 3.1684E-02 3.3879E-02 -5.5528E-01 -4.6002E-02 + +0ITERATION NO.: 33 OBJECTIVE VALUE: 1963.62714630199 NO. OF FUNC. EVALS.: 12 + CUMULATIVE NO. OF FUNC. EVALS.: 626 + NPARAMETR: 7.1603E+00 2.0005E+00 4.5200E-01 2.3101E+00 -1.8592E-01 -9.0227E+00 8.3292E-02 8.6502E-02 2.6813E-01 + PARAMETER: 9.4214E-02 1.8187E-01 1.5067E-01 1.1551E-01 -6.1973E-01 -3.0076E+00 -1.8358E+00 -2.2751E+00 -5.5814E-01 + GRADIENT: 1.0710E+03 1.4693E+00 1.4417E-01 1.4082E+01 1.5067E-01 2.9351E-02 4.5407E-02 -5.4347E-01 -4.5464E-02 + +0ITERATION NO.: 34 OBJECTIVE VALUE: 1963.62714630199 NO. OF FUNC. EVALS.: 30 + CUMULATIVE NO. OF FUNC. EVALS.: 656 + NPARAMETR: 7.1603E+00 2.0005E+00 4.5200E-01 2.3101E+00 -1.8592E-01 -9.0227E+00 8.3292E-02 8.6502E-02 2.6813E-01 + PARAMETER: 9.4214E-02 1.8187E-01 1.5067E-01 1.1551E-01 -6.1973E-01 -3.0076E+00 -1.8358E+00 -2.2751E+00 -5.5814E-01 + GRADIENT: 6.0567E+02 3.0477E-01 -7.6708E-01 -7.8383E+00 1.4000E-02 3.6019E-03 4.5407E-02 -1.8395E+00 -4.6458E-02 + +0ITERATION NO.: 35 OBJECTIVE VALUE: 1963.62714383577 NO. OF FUNC. EVALS.: 29 + CUMULATIVE NO. OF FUNC. EVALS.: 685 + NPARAMETR: 7.1601E+00 2.0005E+00 4.5200E-01 2.3101E+00 -1.8612E-01 -9.0396E+00 8.3292E-02 8.6502E-02 2.6819E-01 + PARAMETER: 9.4212E-02 1.8186E-01 1.5067E-01 1.1551E-01 -6.2041E-01 -3.0132E+00 -1.8358E+00 -2.2751E+00 -5.5802E-01 + GRADIENT: 5.9218E+02 3.2175E-01 -7.2367E-01 -8.9734E+00 1.2385E-02 3.5633E-03 4.1934E-02 -1.7956E+00 -4.9385E-02 + +0ITERATION NO.: 36 OBJECTIVE VALUE: 1963.62702946035 NO. OF FUNC. EVALS.: 24 + CUMULATIVE NO. OF FUNC. EVALS.: 709 + NPARAMETR: 7.1595E+00 2.0004E+00 4.5193E-01 2.3104E+00 -1.8658E-01 -9.0786E+00 8.3302E-02 8.6503E-02 2.7089E-01 + PARAMETER: 9.4204E-02 1.8186E-01 1.5064E-01 1.1552E-01 -6.2192E-01 -3.0262E+00 -1.8358E+00 -2.2751E+00 -5.5301E-01 + GRADIENT: 5.7477E+02 5.2360E-02 -9.1254E-01 -4.0427E+00 6.1464E-03 3.0940E-03 4.1408E-02 -1.7087E+00 -3.0437E-02 + +0ITERATION NO.: 37 OBJECTIVE VALUE: 1963.62408202903 NO. OF FUNC. EVALS.: 33 + CUMULATIVE NO. OF FUNC. EVALS.: 742 RESET HESSIAN, TYPE I + NPARAMETR: 7.1606E+00 2.0003E+00 4.5283E-01 2.3107E+00 -1.8662E-01 -1.0003E+01 8.3205E-02 8.6845E-02 2.7382E-01 + PARAMETER: 9.4218E-02 1.8185E-01 1.5094E-01 1.1554E-01 -6.2208E-01 -3.3343E+00 -1.8364E+00 -2.2731E+00 -5.4763E-01 + GRADIENT: 1.0498E+03 1.0392E+00 -8.8034E-02 1.9228E+01 1.0038E-01 3.2808E-02 1.3819E-03 1.1840E+00 1.3805E-03 + +0ITERATION NO.: 38 OBJECTIVE VALUE: 1963.62384981530 NO. OF FUNC. EVALS.: 11 + CUMULATIVE NO. OF FUNC. EVALS.: 753 + NPARAMETR: 7.1605E+00 2.0003E+00 4.5295E-01 2.3107E+00 -1.8667E-01 -1.0175E+01 8.3193E-02 8.6887E-02 2.7420E-01 + PARAMETER: 9.4217E-02 1.8185E-01 1.5098E-01 1.1554E-01 -6.2225E-01 -3.3915E+00 -1.8364E+00 -2.2729E+00 -5.4694E-01 + GRADIENT: 1.0549E+03 1.3889E+00 2.3893E-01 1.9409E+01 1.6209E-01 2.1596E-02 1.2772E-03 1.3786E+00 6.5595E-04 + +0ITERATION NO.: 39 OBJECTIVE VALUE: 1963.62384981530 NO. OF FUNC. EVALS.: 25 + CUMULATIVE NO. OF FUNC. EVALS.: 778 + NPARAMETR: 7.1605E+00 2.0003E+00 4.5295E-01 2.3107E+00 -1.8667E-01 -1.0175E+01 8.3193E-02 8.6887E-02 2.7420E-01 + PARAMETER: 9.4217E-02 1.8185E-01 1.5098E-01 1.1554E-01 -6.2225E-01 -3.3915E+00 -1.8364E+00 -2.2729E+00 -5.4694E-01 + GRADIENT: 5.8963E+02 -6.0073E-02 -8.3219E-01 -2.5658E+00 3.0793E-03 9.9616E-04 1.2772E-03 8.9434E-02 -3.4752E-04 + +0ITERATION NO.: 40 OBJECTIVE VALUE: 1963.62384981530 NO. OF FUNC. EVALS.: 21 + CUMULATIVE NO. OF FUNC. EVALS.: 799 + NPARAMETR: 7.1605E+00 2.0003E+00 4.5295E-01 2.3107E+00 -1.8667E-01 -1.0175E+01 8.3193E-02 8.6887E-02 2.7420E-01 + PARAMETER: 9.4217E-02 1.8185E-01 1.5098E-01 1.1554E-01 -6.2225E-01 -3.3915E+00 -1.8364E+00 -2.2729E+00 -5.4694E-01 + GRADIENT: -1.7918E+01 -5.1442E-02 -8.0177E-01 -1.6108E+00 5.0919E-03 9.6655E-04 -4.2896E-03 1.0678E-01 -1.2248E-03 + + #TERM: +0MINIMIZATION SUCCESSFUL + HOWEVER, PROBLEMS OCCURRED WITH THE MINIMIZATION. + REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM ONLY + AFTER CHECKING THAT THE COVARIANCE STEP PRODUCES REASONABLE OUTPUT. + NO. OF FUNCTION EVALUATIONS USED: 799 + NO. OF SIG. DIGITS IN FINAL EST.: 2.8 + + ETABAR IS THE ARITHMETIC MEAN OF THE ETA-ESTIMATES, + AND THE P-VALUE IS GIVEN FOR THE NULL HYPOTHESIS THAT THE TRUE MEAN IS 0. + + ETABAR: -7.2140E-04 + SE: 6.2022E-02 + N: 19 + + P VAL.: 9.9072E-01 + + ETASHRINKSD(%) 3.7014E+00 + ETASHRINKVR(%) 7.2658E+00 + EBVSHRINKSD(%) 5.9433E+00 + EBVSHRINKVR(%) 1.1533E+01 + EPSSHRINKSD(%) 2.9359E+00 2.9359E+00 + EPSSHRINKVR(%) 5.7856E+00 5.7856E+00 + + + TOTAL DATA POINTS NORMALLY DISTRIBUTED (N): 256 + N*LOG(2PI) CONSTANT TO OBJECTIVE FUNCTION: 470.49652900079241 + OBJECTIVE FUNCTION VALUE WITHOUT CONSTANT: 1963.6238498152991 + OBJECTIVE FUNCTION VALUE WITH CONSTANT: 2434.1203788160915 + REPORTED OBJECTIVE FUNCTION DOES NOT CONTAIN CONSTANT + + TOTAL EFFECTIVE ETAS (NIND*NETA): 19 + + #TERE: + Elapsed estimation time in seconds: 434.54 + Elapsed covariance time in seconds: 227.18 + Elapsed postprocess time in seconds: 9.61 +1 + + + + + + + + + + + + + + + + + + + + + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + #OBJT:************** MINIMUM VALUE OF OBJECTIVE FUNCTION ******************** + ******************** ******************** + ************************************************************************************************************************ + + + + + + + #OBJV:******************************************** 1963.624 ************************************************** +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** FINAL PARAMETER ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + + THETA - VECTOR OF FIXED EFFECTS PARAMETERS ********* + + + TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 + + 7.16E+00 2.00E+00 4.53E-01 2.31E+00 -1.87E-01 -1.02E+01 + + + + OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ******** + + + ETA1 + + ETA1 ++ 8.32E-02 + + + + SIGMA - COV MATRIX FOR RANDOM EFFECTS - EPSILONS **** + + + EPS1 EPS2 + + EPS1 ++ 8.69E-02 + + EPS2 ++ 0.00E+00 2.74E-01 + +1 + + + OMEGA - CORR MATRIX FOR RANDOM EFFECTS - ETAS ******* + + + ETA1 + + ETA1 ++ 2.88E-01 + + + + SIGMA - CORR MATRIX FOR RANDOM EFFECTS - EPSILONS *** + + + EPS1 EPS2 + + EPS1 ++ 2.95E-01 + + EPS2 ++ 0.00E+00 5.24E-01 + +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** STANDARD ERROR OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + + THETA - VECTOR OF FIXED EFFECTS PARAMETERS ********* + + + TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 + + 7.42E-02 2.17E-01 2.21E-01 1.63E-01 1.55E-01 3.44E+01 + + + + OMEGA - COV MATRIX FOR RANDOM EFFECTS - ETAS ******** + + + ETA1 + + ETA1 ++ 2.30E-02 + + + + SIGMA - COV MATRIX FOR RANDOM EFFECTS - EPSILONS **** + + + EPS1 EPS2 + + EPS1 ++ 1.46E-02 + + EPS2 ++ ......... 9.16E-01 + +1 + + + OMEGA - CORR MATRIX FOR RANDOM EFFECTS - ETAS ******* + + + ETA1 + + ETA1 ++ 3.99E-02 + + + + SIGMA - CORR MATRIX FOR RANDOM EFFECTS - EPSILONS *** + + + EPS1 EPS2 + + EPS1 ++ 2.48E-02 + + EPS2 ++ ......... 8.75E-01 + +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** COVARIANCE MATRIX OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 OM11 SG11 SG12 SG22 + + TH 1 ++ 5.50E-03 + + TH 2 ++ 7.17E-03 4.73E-02 + + TH 3 ++ 9.14E-04 -2.07E-02 4.89E-02 + + TH 4 ++ 4.75E-04 -5.98E-03 2.78E-02 2.65E-02 + + TH 5 ++ 4.44E-03 3.28E-02 -2.13E-02 -9.86E-03 2.41E-02 + + TH 6 ++ 5.90E-03 -1.21E+00 5.78E+00 5.45E+00 -2.05E+00 1.18E+03 + + OM11 ++ -6.12E-04 -2.93E-04 6.56E-04 -1.64E-04 -2.07E-04 3.16E-02 5.29E-04 + + SG11 ++ 2.75E-04 1.69E-04 1.90E-03 1.35E-03 -2.50E-04 3.09E-01 -3.75E-05 2.14E-04 + + SG12 ++ ......... ......... ......... ......... ......... ......... ......... ......... ......... + + SG22 ++ 9.30E-04 3.84E-02 -1.53E-01 -1.45E-01 5.85E-02 -3.15E+01 -5.19E-04 -8.07E-03 ......... 8.39E-01 + +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** CORRELATION MATRIX OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 OM11 SG11 SG12 SG22 + + TH 1 ++ 7.42E-02 + + TH 2 ++ 4.45E-01 2.17E-01 + + TH 3 ++ 5.58E-02 -4.31E-01 2.21E-01 + + TH 4 ++ 3.94E-02 -1.69E-01 7.73E-01 1.63E-01 + + TH 5 ++ 3.85E-01 9.71E-01 -6.19E-01 -3.90E-01 1.55E-01 + + TH 6 ++ 2.31E-03 -1.61E-01 7.59E-01 9.72E-01 -3.83E-01 3.44E+01 + + OM11 ++ -3.59E-01 -5.87E-02 1.29E-01 -4.37E-02 -5.80E-02 4.00E-02 2.30E-02 + + SG11 ++ 2.54E-01 5.30E-02 5.89E-01 5.67E-01 -1.10E-01 6.14E-01 -1.11E-01 1.46E-02 + + SG12 ++ ......... ......... ......... ......... ......... ......... ......... ......... ......... + + SG22 ++ 1.37E-02 1.93E-01 -7.57E-01 -9.73E-01 4.11E-01 -9.99E-01 -2.46E-02 -6.03E-01 ......... 9.16E-01 + +1 + ************************************************************************************************************************ + ******************** ******************** + ******************** FIRST ORDER CONDITIONAL ESTIMATION WITH INTERACTION ******************** + ******************** INVERSE COVARIANCE MATRIX OF ESTIMATE ******************** + ******************** ******************** + ************************************************************************************************************************ + + + TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 OM11 SG11 SG12 SG22 + + TH 1 ++ 4.86E+02 + + TH 2 ++ 2.22E+04 3.59E+06 + + TH 3 ++ -3.87E+03 -6.00E+05 1.02E+05 + + TH 4 ++ 4.74E+02 6.40E+04 -1.20E+04 2.78E+03 + + TH 5 ++ -3.59E+04 -5.76E+06 9.66E+05 -1.05E+05 9.26E+06 + + TH 6 ++ 4.37E+01 5.50E+03 -1.27E+03 2.77E+02 -9.45E+03 6.64E+01 + + OM11 ++ 4.04E+03 6.04E+05 -9.46E+04 8.20E+03 -9.58E+05 -1.79E+02 1.26E+05 + + SG11 ++ 5.34E+03 8.69E+05 -1.43E+05 1.55E+04 -1.39E+06 8.67E+02 1.57E+05 2.26E+05 + + SG12 ++ ......... ......... ......... ......... ......... ......... ......... ......... ......... + + SG22 ++ 2.56E+03 3.55E+05 -7.23E+04 1.32E+04 -5.93E+05 2.72E+03 1.82E+04 6.86E+04 ......... 1.17E+05 + + Elapsed finaloutput time in seconds: 0.08 +1THERE ARE ERROR MESSAGES IN FILE PRDERR + #CPUT: Total CPU Time in Seconds, 671.125 +Stop Time: +Tue 04/09/2024 +01:45 PM diff --git a/vignette/models/mavoglurant-pbpk-101/mrgsolve_code_mavoglurant-pbpk.R b/vignette/models/mavoglurant-pbpk-101/mrgsolve_code_mavoglurant-pbpk.R new file mode 100644 index 0000000..abfbb0d --- /dev/null +++ b/vignette/models/mavoglurant-pbpk-101/mrgsolve_code_mavoglurant-pbpk.R @@ -0,0 +1,127 @@ +code <- ' +$PROB Mavoglurant PBPK (Wendling et al., 2016. DOI: 10.1208/s12248-015-9840-7) presented as an nlmixr2 example (https://nlmixr2.org/articles/mavoglurant.html) + +$PARAM + +WTKG=NA_real_ + +$THETA + +7.2 2 0.45 2.3 -0.19 -10 + +$CMT + +LU +HT +BR +MU +AD +SK +SP +PA +LI +ST +GU +BO +KI +AB +VB +RB + +$MAIN + +/* NOTE: There is no guarantee to the accuracy of the NONMEM to mrgsolve translator. It remains the responsibility of the user to validate the resulting mrgsolve code. */ + +/* NOTE: The nonmem2mrgsolve package remains in active development, please report bugs and feature requests to improve future versions. */ +/* NOTE: If you find nonmem2mrgsolve helpful, please consider giving it a star at github.com/Andy00000000000/nonmem2mrgsolve. */ + +/* NOTE: The translator does not currently convert T or TIME to SOLVERTIME. */ +/* NOTE: The translator does not currently convert MTIME() to self.mtime(). */ + +/* CALLFL=-2; */ +R_VB=RATE; +double lCLint = THETA1; +double MU_1 = lCLint; +double CLint = exp(MU_1+ETA(1)); +double KbBR = exp(THETA2); +double KbMU = exp(THETA3); +double KbAD = exp(THETA4); +double KbBO = exp(THETA5); +double KbRB = exp(THETA6); +double CO = (187.00*pow(WTKG,0.81))*60.0/1000.0; +double QHT = 4.0 *CO/100.0; +double QBR = 12.0*CO/100.0; +double QMU = 17.0*CO/100.0; +double QAD = 5.0 *CO/100.0; +double QSK = 5.0 *CO/100.0; +double QSP = 3.0 *CO/100.0; +double QPA = 1.0 *CO/100.0; +double QLI = 25.5*CO/100.0; +double QST = 1.0 *CO/100.0; +double QGU = 14.0*CO/100.0; +double QHA = QLI - (QSP + QPA + QST + QGU); +double QBO = 5.0 *CO/100.0; +double QKI = 19.0*CO/100.0; +double QRB = CO - (QHT + QBR + QMU + QAD + QSK + QLI + QBO + QKI); +double QLU = QHT + QBR + QMU + QAD + QSK + QLI + QBO + QKI + QRB; +double VLU = (0.76 *WTKG/100.0)/1.051; +double VHT = (0.47 *WTKG/100.0)/1.030; +double VBR = (2.00 *WTKG/100.0)/1.036; +double VMU = (40.00*WTKG/100.0)/1.041; +double VAD = (21.42*WTKG/100.0)/0.916; +double VSK = (3.71 *WTKG/100.0)/1.116; +double VSP = (0.26 *WTKG/100.0)/1.054; +double VPA = (0.14 *WTKG/100.0)/1.045; +double VLI = (2.57 *WTKG/100.0)/1.040; +double VST = (0.21 *WTKG/100.0)/1.050; +double VGU = (1.44 *WTKG/100.0)/1.043; +double VBO = (14.29*WTKG/100.0)/1.990; +double VKI = (0.44 *WTKG/100.0)/1.050; +double VAB = (2.81 *WTKG/100.0)/1.040; +double VVB = (5.62 *WTKG/100.0)/1.040; +double VRB = (3.86 *WTKG/100.0)/1.040; +double BP = 0.61; +double fup = 0.028; +double fub = fup/BP; +double KbLU = exp(0.8334); +double KbHT = exp(1.1205); +double KbSK = exp(-.5238); +double KbSP = exp(0.3224); +double KbPA = exp(0.3224); +double KbLI = exp(1.7604); +double KbST = exp(0.3224); +double KbGU = exp(1.2026); +double KbKI = exp(1.3171); +double S15 = VVB*BP/1000.0; + +$ODE + +dxdt_LU=QLU*(VB/VVB - LU/KbLU/VLU); +dxdt_HT=QHT*(AB/VAB - HT/KbHT/VHT); +dxdt_BR=QBR*(AB/VAB - BR/KbBR/VBR); +dxdt_MU=QMU*(AB/VAB - MU/KbMU/VMU); +dxdt_AD=QAD*(AB/VAB - AD/KbAD/VAD); +dxdt_SK=QSK*(AB/VAB - SK/KbSK/VSK); +dxdt_SP=QSP*(AB/VAB - SP/KbSP/VSP); +dxdt_PA=QPA*(AB/VAB - PA/KbPA/VPA); +dxdt_LI=QHA*AB/VAB + QSP*SP/KbSP/VSP + QPA*PA/KbPA/VPA + QST*ST/KbST/VST + QGU*GU/KbGU/VGU - CLint*fub*LI/KbLI/VLI - QLI*LI/KbLI/VLI; +dxdt_ST=QST*(AB/VAB - ST/KbST/VST); +dxdt_GU=QGU*(AB/VAB - GU/KbGU/VGU); +dxdt_BO=QBO*(AB/VAB - BO/KbBO/VBO); +dxdt_KI=QKI*(AB/VAB - KI/KbKI/VKI); +dxdt_AB=QLU*(LU/KbLU/VLU - AB/VAB); +dxdt_VB=QHT*HT/KbHT/VHT + QBR*BR/KbBR/VBR + QMU*MU/KbMU/VMU + QAD*AD/KbAD/VAD + QSK*SK/KbSK/VSK + QLI*LI/KbLI/VLI + QBO*BO/KbBO/VBO + QKI*KI/KbKI/VKI + QRB*RB/KbRB/VRB - QLU*VB/VVB; +dxdt_RB=QRB*(AB/VAB - RB/KbRB/VRB); +double C15=VB/S15; + +$OMEGA @block + +0.083 + +$CAPTURE + +C15 +WTKG +CLint + +' \ No newline at end of file diff --git a/vignette/models/mavoglurant-pbpk-101/mrgsolve_code_mavoglurant-pbpk_user-modified.R b/vignette/models/mavoglurant-pbpk-101/mrgsolve_code_mavoglurant-pbpk_user-modified.R new file mode 100644 index 0000000..f94212d --- /dev/null +++ b/vignette/models/mavoglurant-pbpk-101/mrgsolve_code_mavoglurant-pbpk_user-modified.R @@ -0,0 +1,128 @@ +code <- ' +$PROB Mavoglurant PBPK (Wendling et al., 2016. DOI: 10.1208/s12248-015-9840-7) presented as an nlmixr2 example (https://nlmixr2.org/articles/mavoglurant.html) + +$PARAM + +WTKG=NA_real_ +INRATE=NA_real_ + +$THETA + +7.2 2 0.45 2.3 -0.19 -10 + +$CMT + +LU +HT +BR +MU +AD +SK +SP +PA +LI +ST +GU +BO +KI +AB +VB +RB + +$MAIN + +/* NOTE: There is no guarantee to the accuracy of the NONMEM to mrgsolve translator. It remains the responsibility of the user to validate the resulting mrgsolve code. */ + +/* NOTE: The nonmem2mrgsolve package remains in active development, please report bugs and feature requests to improve future versions. */ +/* NOTE: If you find nonmem2mrgsolve helpful, please consider giving it a star at github.com/Andy00000000000/nonmem2mrgsolve. */ + +/* NOTE: The translator does not currently convert T or TIME to SOLVERTIME. */ +/* NOTE: The translator does not currently convert MTIME() to self.mtime(). */ + +/* CALLFL=-2; */ +R_VB=INRATE; +double lCLint = THETA1; +double MU_1 = lCLint; +double CLint = exp(MU_1+ETA(1)); +double KbBR = exp(THETA2); +double KbMU = exp(THETA3); +double KbAD = exp(THETA4); +double KbBO = exp(THETA5); +double KbRB = exp(THETA6); +double CO = (187.00*pow(WTKG,0.81))*60.0/1000.0; +double QHT = 4.0 *CO/100.0; +double QBR = 12.0*CO/100.0; +double QMU = 17.0*CO/100.0; +double QAD = 5.0 *CO/100.0; +double QSK = 5.0 *CO/100.0; +double QSP = 3.0 *CO/100.0; +double QPA = 1.0 *CO/100.0; +double QLI = 25.5*CO/100.0; +double QST = 1.0 *CO/100.0; +double QGU = 14.0*CO/100.0; +double QHA = QLI - (QSP + QPA + QST + QGU); +double QBO = 5.0 *CO/100.0; +double QKI = 19.0*CO/100.0; +double QRB = CO - (QHT + QBR + QMU + QAD + QSK + QLI + QBO + QKI); +double QLU = QHT + QBR + QMU + QAD + QSK + QLI + QBO + QKI + QRB; +double VLU = (0.76 *WTKG/100.0)/1.051; +double VHT = (0.47 *WTKG/100.0)/1.030; +double VBR = (2.00 *WTKG/100.0)/1.036; +double VMU = (40.00*WTKG/100.0)/1.041; +double VAD = (21.42*WTKG/100.0)/0.916; +double VSK = (3.71 *WTKG/100.0)/1.116; +double VSP = (0.26 *WTKG/100.0)/1.054; +double VPA = (0.14 *WTKG/100.0)/1.045; +double VLI = (2.57 *WTKG/100.0)/1.040; +double VST = (0.21 *WTKG/100.0)/1.050; +double VGU = (1.44 *WTKG/100.0)/1.043; +double VBO = (14.29*WTKG/100.0)/1.990; +double VKI = (0.44 *WTKG/100.0)/1.050; +double VAB = (2.81 *WTKG/100.0)/1.040; +double VVB = (5.62 *WTKG/100.0)/1.040; +double VRB = (3.86 *WTKG/100.0)/1.040; +double BP = 0.61; +double fup = 0.028; +double fub = fup/BP; +double KbLU = exp(0.8334); +double KbHT = exp(1.1205); +double KbSK = exp(-.5238); +double KbSP = exp(0.3224); +double KbPA = exp(0.3224); +double KbLI = exp(1.7604); +double KbST = exp(0.3224); +double KbGU = exp(1.2026); +double KbKI = exp(1.3171); +double S15 = VVB*BP/1000.0; + +$ODE + +dxdt_LU=QLU*(VB/VVB - LU/KbLU/VLU); +dxdt_HT=QHT*(AB/VAB - HT/KbHT/VHT); +dxdt_BR=QBR*(AB/VAB - BR/KbBR/VBR); +dxdt_MU=QMU*(AB/VAB - MU/KbMU/VMU); +dxdt_AD=QAD*(AB/VAB - AD/KbAD/VAD); +dxdt_SK=QSK*(AB/VAB - SK/KbSK/VSK); +dxdt_SP=QSP*(AB/VAB - SP/KbSP/VSP); +dxdt_PA=QPA*(AB/VAB - PA/KbPA/VPA); +dxdt_LI=QHA*AB/VAB + QSP*SP/KbSP/VSP + QPA*PA/KbPA/VPA + QST*ST/KbST/VST + QGU*GU/KbGU/VGU - CLint*fub*LI/KbLI/VLI - QLI*LI/KbLI/VLI; +dxdt_ST=QST*(AB/VAB - ST/KbST/VST); +dxdt_GU=QGU*(AB/VAB - GU/KbGU/VGU); +dxdt_BO=QBO*(AB/VAB - BO/KbBO/VBO); +dxdt_KI=QKI*(AB/VAB - KI/KbKI/VKI); +dxdt_AB=QLU*(LU/KbLU/VLU - AB/VAB); +dxdt_VB=QHT*HT/KbHT/VHT + QBR*BR/KbBR/VBR + QMU*MU/KbMU/VMU + QAD*AD/KbAD/VAD + QSK*SK/KbSK/VSK + QLI*LI/KbLI/VLI + QBO*BO/KbBO/VBO + QKI*KI/KbKI/VKI + QRB*RB/KbRB/VRB - QLU*VB/VVB; +dxdt_RB=QRB*(AB/VAB - RB/KbRB/VRB); +double C15=VB/S15; + +$OMEGA @block + +0.083 + +$CAPTURE + +C15 +WTKG +CLint + +' diff --git a/vignette/models/mavoglurant-pbpk-101/run_nonmem2mrgsolve_mavoglurant.R b/vignette/models/mavoglurant-pbpk-101/run_nonmem2mrgsolve_mavoglurant.R new file mode 100644 index 0000000..1452401 --- /dev/null +++ b/vignette/models/mavoglurant-pbpk-101/run_nonmem2mrgsolve_mavoglurant.R @@ -0,0 +1,28 @@ +## Start #### + +# devtools::install_github("Andy00000000000/nonmem2mrgsolve") +# setwd("...") + +library("nonmem2mrgsolve") + +nonmem2mrgsolve( + "mod1.ctl", # filename + "./vignette/models/mavoglurant-pbpk-101/", # dir + out.filename = "mrgsolve_code_mavoglurant-pbpk", + sigdig = 2 +) + +source("./vignette/models/mavoglurant-pbpk-101/mrgsolve_code_mavoglurant-pbpk.R") +mrgsolve::mcode("Test_Unmodified_Translation",code) + +source("./vignette/models/mavoglurant-pbpk-101/mrgsolve_code_mavoglurant-pbpk_user-modified.R") +mrgsolve::mcode("Test_Modified_Translation",code) + +# Shortcomings of the current translation which requires the user's attention: +# +# Line 42: This line needs to be manually changed by the user +# 1) Rename "RATE" to a non-reserved term such as "INRATE" +# 2) Add "INRATE" to $PARAM +# 3) Pass "INRATE" into the mrgsolve simulation using either param(INRATE = ...) or data_set() + +## End ####