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Introduction

The introduction examples and the other examples show how to perform various types of simulations, such as typical subject simulations, simulations of new subjects, simulation of known subjects, and simulation with parameter uncertainty. As different as these simulations may be, they are all simulations of a model, exactly as specified or exactly as estimated. The examples in this document focus on how modifications to the estimated model can be specified. As will be shown, NMsim provides very flexible and easy-to-use methods to obtain such modifications, all contained within the NMsim() interface itself.

Objectives

This document aims at enabling you to do the following tasks.

  • Control whether and how to update parameter values according to the final model parameter estimates using the inits argument.

  • Modify model parameter values ($THETA, $OMEGA and SIGMA) to specify values using the inits argument

  • Use the modify argument to do custom manipulations of any parts of the control stream before simulation.

  • Modify data exclusions/inclusions ($IGNORE/$ACCEPT) using the filters argument.

  • Adjust $SIZES variables using the sizes argument.

The examples described below use the modify argument to modify the NONMEM control stream and to address the following pharmacometric questions:

  • Modify KA: How is the concentration-time profile affected if switching formulation (reducing absorption rate) by a range of fold-values?
  • Modify F1 and CL: What is the expected concentration-time profile in patients with a certain Drug-Drug Interaction effect on clearance and bioavailability?
  • Add ALAG: How will a dose delay of different amounts of time affect the predicted exposure?
  • Add AUC computation in control stream: How can we use NONMEM to integrate AUC during model simulation leveraging the benefits of using a sparse grid via NMsim?

Prerequisites

To reproduce the examples, you will need to have NMsim configured to find your Nonmem installation. Also, you should be familiar with how to use NMsim for running basic simulation workflows. If you need to revisit those topics, please go to NMsim-intro.html. Especially, it will be helpful to be familiar with simple workflows with NMsim to understand that certain “model mofifications” such as handling data sections are done automatically by NMsim, and so methods described in this document are unnecessary for those.

Selecting a Model and Generating Simulation Data

file.mod <- system.file("examples/nonmem/xgxr021.mod",
                        package="NMsim")
data.sim <- NMcreateDoses(TIME=c(0,24),AMT=c(300,150),ADDL=c(0,5),II=c(0,24),CMT=1)|>
    NMaddSamples(TIME=0:(24*7),CMT=2)
## data.sim <- NMreadCsv(system.file("examples/derived/dat_sim1.csv",
##                                   package="NMsim"))

Control Parameter Values (inits)

First, we collect an overview of the parameters in the model, their initial values as specified in the control stream, and the estimated values, as read from the .ext file. We are using functions from NMdata to get these. If you are interested in learning more about these functions, This NMdata vignette is a good place to start.

partab <- NMreadParsText(file.mod,as.fun="data.table",format="%init;%symbol") |>
    mergeCheck(NMreadExt(file.mod),by="parameter",all.x=TRUE,common.cols="drop.y",quiet=TRUE) ## |>
## mergeCheck(NMreadInits(file.mod),by="parameter",all.x=TRUE,common.cols="drop.y",quiet=TRUE)
## partab[,.(par.name,symbol,init,lower,upper,FIX,est)]
partab[,.(par.name,symbol,init,est)]
##       par.name   symbol    init         est
##         <fctr>   <char>  <char>       <num>
##  1:   THETA(1)    POPKA   (0,1)   2.1665600
##  2:   THETA(2)    POPV2 (0,100)  75.7289000
##  3:   THETA(3)    POPCL   (0,3)  13.9777000
##  4:   THETA(4)    POPV3  (0,50) 150.0600000
##  5:   THETA(5)      TVQ  (0,.5)   8.4865100
##  6: OMEGA(1,1)   BSV KA   0 FIX   0.0000000
##  7: OMEGA(2,2)   BSV V2     0.1   0.1786660
##  8: OMEGA(3,3)   BSV CL     0.1   0.2497790
##  9: OMEGA(4,4)   BSV V3   0 FIX   0.0000000
## 10: OMEGA(5,5)    BSV Q   0 FIX   0.0000000
## 11: SIGMA(1,1) Prop Err     0.1   0.0822435
## 12: SIGMA(2,2)  Add Err   0 FIX   0.0000000

Let’s run a simple simulation without specifying inits.

simres <- NMsim(file.mod=file.mod,
                data=data.sim,
                name.sim="basic-sim")
diffr::diffr(file.mod,modTab(simres)$path.sim)

Now, adding some custom values

simres.inits1 <- NMsim(file.mod=file.mod,
                       data=data.sim,
                       inits=list("theta(1)"=list(init=0.54)
                                 ,"omega(3,3)"=list(init=.5)
                                  ),
                       name.sim="inits1")
diffr::diffr(file.mod,modTab(simres.inits1)$path.sim)

Example (modify): Change in formulation

The effect on the concentration-time profile of a change in formulation that reduces absorption rate KA is explored with the use of a scaling factor KASCALE=c(1,4,10) included to the NONMEM control stream via the modify argument. The absorption rate reduction is provided through the NMsim simulation data dat.sim.varka containing dosing events, simulation time steps and the value of KASCALE for each simulated patient.

First KASCALE is added to the simulation data

# add KASCALE and copy patient info for each value of KASCALE
dat.sim.varka <- data.sim[,data.table(KASCALE=c(1,4,10)),by=data.sim] 
dat.sim.varka[,ID:=.GRP,by=.(KASCALE,ID)] # update patient IDs
setorder(dat.sim.varka,ID,TIME,EVID) # order rows

Then the NMsim function is used to run the simulation in which the modify argument is used to simulate a modified model with different absorption rates, scaled by the parameter KASCALE. Two different approaches are demonstrated:

  1. the effect of the scaling factor KASCALE is added at the end of the PK section in the NONMEM control stream.
simres.varka <- NMsim(file.mod=file.mod # NONMEM control stream
                     ,data=dat.sim.varka # simulation data file
                     ,name.sim="varka"
                     ,modify=list(PK=add("KA=KA/KASCALE")))
  1. the specific line that defines TVKA is modified to include the effect of the scaling factor KASCALE
simres.varka2 <- NMsim(file.mod=file.mod
                      ,data=dat.sim.varka
                      ,name.sim="varka2"
                      ,modify=list(PK=overwrite("THETA(1)","THETA(1)/KASCALE"))
                       )

The code below returns the plot

simres.varka=as.data.table(simres.varka)
simres.varka2=as.data.table(simres.varka2)
simres.both <- rbind(simres.varka[,method:="a. add()"],
                     simres.varka2[,method:="b. custom/sub()"]
                     )

ggplot(simres.both[EVID==2],aes(TIME,PRED,colour=factor(KASCALE)))+
    geom_line()+
    labs(colour="Fold absorption prolongation, KASCALE")+
    scale_x_continuous(breaks=seq(0,168,by=24))+
    facet_wrap(~method)+
    scale_color_manual(values=c("orange", "blue", "darkgreen"))
Concentration (`PRED`) profile as a function of time computed by `NMsim` modified models **a** (left) and **b** (right). The equivalence and robustness of the two modified models is supported by the matching results, corresponding to reduced `PRED` values for higher values of `KASCALE` (lower absorption rate).

Concentration (PRED) profile as a function of time computed by NMsim modified models a (left) and b (right). The equivalence and robustness of the two modified models is supported by the matching results, corresponding to reduced PRED values for higher values of KASCALE (lower absorption rate).

NOTE: the NMsim overwrite function prior to version 0.1.6 has a bug that was fixed in the0.1.5.902 github release; it can be installed with

library(remotes)
install_github("NMautoverse/NMsim")

Drug-Drug Interaction (DDI)

The effect of DDI on clearance (CL) and bioavailability (F1) is simulated for the following scenarios
scenario CLSCALE FSCALE CLSCALE/FSCALE
noDDI 1 1 1
DDI.1 0.5 1.2 0.42
DDI.2 0.33 1.1 0.3

First the CL and F1 data is added to the patient data

## 'Outer join'
dat.sim.DDI=data.sim[,data.table(CLSCALE=c(1,1/2,1/3)
                                ,FSCALE=c(1,1.2,1.1)
                                ,lab=c("noDDI","DDI.1","DDI.2"))
                    ,by=data.sim]
dat.sim.DDI[,ID:=.GRP,by=.(lab,ID)]
setorder(dat.sim.DDI,ID,TIME,EVID)

Then, the DDI driven change in parameters is added at the end of the PK section of the NONMEM control stream via the modify argument in the NMsim() function.

simres.DDI <- NMsim(file.mod=file.mod
                   ,data=dat.sim.DDI
                   ,name.sim="DDI"
                   ,modify=list(PK=add("CL=CL*CLSCALE"
                                      ,"F1=FSCALE")))

The effect on the concentration-time profile is shown in the figure below

Concentration (`PRED`) profile as a function of time computed by `NMsim` modified model for different DDIs. The modified model correctly simulates (i) a higher value of `Cmax` on day 1 for higher biovalability; (ii) a higher `PRED` value  at steady state for lower apparent clearance effect `CLSCALE/FSCALE` values.

Concentration (PRED) profile as a function of time computed by NMsim modified model for different DDIs. The modified model correctly simulates (i) a higher value of Cmax on day 1 for higher biovalability; (ii) a higher PRED value at steady state for lower apparent clearance effect CLSCALE/FSCALE values.

Dose delay

Deviations in the administration schedule of a drug are simulated including three parameters in the dataset: the dose number DOSCUMN, obtained with NMdata::addTAPD(), the specific number of the delayed dose DELAYDOS and the time delay ALAG.

dat.sim.alag = data.sim |> NMexpandDoses() |> addTAPD() # expand doses and add dose number
dat.sim.alag[,ROW:=.I] # restore ROW with correct value
                                        # add delayed dose
dat.sim.dos.delay=dat.sim.alag[,data.table(DELAYDOS=c(2,3,4,5,6,7))
                              ,by=dat.sim.alag]
                                        # add dose delay 
dat.sim.alag.final=dat.sim.dos.delay[,data.table(ALAG=c(0,6,12,18,24))
                                    ,by=dat.sim.dos.delay]
                                        # update ID 
dat.sim.alag.final[,ID:=.GRP,by=.(ALAG,DELAYDOS,ID)]
setorder(dat.sim.alag.final,ID,TIME,EVID)
                                        #dat.sim.alag.final = dat.sim.alag.final |> fill(DOSCUMN)

The following patient has a 6 hours delay to the administration of dose 2.

TIME AMT DOSCUMN DELAYDOS ALAG
0 300 1 2 6
24 150 2 2 6
48 150 3 2 6
72 150 4 2 6
96 150 5 2 6
120 150 6 2 6
144 150 7 2 6

The time delay is included in the modified control stream with NMsim adding a single line at the end of the PK section, where the dose delay on compartment 1 ALAG1 is modified for the dose with dose number DOSCUMN equal to the target delayed dose number DELAYDOS

simres.alag <- NMsim(file.mod=file.mod
                    ,data=dat.sim.alag.final
                    ,name.sim="alag"
                    ,modify=list(PK=
                                     add("IF(DOSCUMN.EQ.DELAYDOS) ALAG1=ALAG")))

The effect on concentration-time profiles and daily AUC are shown in the two images below.

Effect of time delay (0, 12 and 24 hours on dose 2) on concentration (`PRED`) profile as a function of time computed by `NMsim` modified model. The implementation of the modified model simply consists of the addition of the variables `DOSCUMN`, `DELAYDOS`, and `ALAG` to the original data set, and the addition of one line of code to the PK section of the control stream via `modify`.

Effect of time delay (0, 12 and 24 hours on dose 2) on concentration (PRED) profile as a function of time computed by NMsim modified model. The implementation of the modified model simply consists of the addition of the variables DOSCUMN, DELAYDOS, and ALAG to the original data set, and the addition of one line of code to the PK section of the control stream via modify.

Daily exposure on day 3 as a function of time delay for dose 2 (left) and dose 3 (right). The simulation results predict an increased risk for possible safety concerns (left panel, over-exposure) and loss of efficacy (right panel, under-exposure) as dose time delay gets larger.

Daily exposure on day 3 as a function of time delay for dose 2 (left) and dose 3 (right). The simulation results predict an increased risk for possible safety concerns (left panel, over-exposure) and loss of efficacy (right panel, under-exposure) as dose time delay gets larger.

AUC

The following example computes daily exposure:

  • at post-processing, using trapezoidal method, after the unmodified NONMEM model is simulated on three different fine grids with evenly spaced time steps of 0.25, 1, and 4 hours, respectively, labelled AUC trapez
file.mod.auc <- system.file("examples/nonmem/xgxr046.mod",
                            package="NMsim")
data.sim.auc <- NMreadCsv(system.file("examples/derived/dat_sim1.csv",
                                      package="NMsim"))
data.sim.auc[,AMT:=1000*AMT]

                                        # time step 1hr
data.sim.1hr=data.sim.auc
data.sim.1hr[,TSTEP:="1hr"]

                                        # time step 0.25hr
data.sim.0.25hr=addEVID2(data.sim.auc[EVID==1],CMT=2,time.sim=seq(0,192,by=0.25))
data.sim.0.25hr[,TSTEP:="0.25hr"]

                                        # time step 4hr
data.sim.4hr <- addEVID2(data.sim.auc[EVID==1],CMT=2,time.sim=seq(0,192,by=4))
data.sim.4hr[,TSTEP:="4hr"]

sres.trapez <- NMsim(file.mod=file.mod.auc
                    ,data=list(data.sim.1hr # run NMsim on a list of data sets to run all different scenarios at once
                              ,data.sim.0.25hr
                              ,data.sim.4hr)
                    ,seed=12345
                    ,table.vars=cc(PRED,IPRED)
                    ,name.sim="AUC.trapez"
                    ,reuse.results=reuse.results
                     )

                                        # daily AUC computation
sim.auc=sres.trapez[EVID==2,.(ID,TIME,PRED,time.step=TSTEP)] 
sim.auc[,DAY:=(TIME%/%24)+1] # define DAY variable
                                        # create duplicate time steps for end-of-day
                                        # (e.g 24h belongs to both day 1 and day2)
sim.dupli.24h=sim.auc[TIME%%24==0 & TIME>0,.(ID
                                            ,DAY=DAY-1
                                            ,TIME
                                            ,PRED
                                            ,time.step)]
sim.auc.final <- rbind(sim.auc
                      ,sim.dupli.24h) |> setorder(ID,DAY,TIME,time.step)

sim.auc.trapez<-sim.auc.final[DAY<8,.(AUC=NMcalc::trapez(TIME,PRED))
                             ,by=.(ID,DAY,time.step)]
                                        # stmp=sres1[EVID==2,.(ID,TIME,PRED)]
                                        # stmp[,DAY:=(TIME%/%24)+1]
                                        # sAUC<-stmp[,.(AUC=NMcalc::trapez(TIME,PRED)),by=.(ID,DAY)]
  • at run time, with an NMsim modified script, on a course grid with evenly spaced time steps of 24 hours, labelled AUC $DES. Of note, this task requires additions to the control stream in multiple sections.
# AUC with NMsim -  time step 24hr
data.sim2 <- addEVID2(data.sim.auc[EVID==1],CMT=2,time.sim=seq(0,by=24,length.out=9))

sres.des <- NMsim(file.mod=file.mod.auc
                 ,data=data.sim2
                 ,table.vars=cc(PRED,IPRED,AUCNMSIM)
                 ,name.sim="AUC.nmsim"
                 ,seed=12345
                 ,reuse.results=reuse.results
                 ,modify=list(MODEL=add("COMP=(AUC)")
                             ,DES=add("DADT(3)=A(2)/V2")
                             ,ERROR=add("AUCCUM=A(3)"
                                       ,"IF(NEWIND.NE.2) OLDAUCCUM=0"
                                       ,"AUCNMSIM = AUCCUM-OLDAUCCUM"
                                       ,"OLDAUCCUM = AUCCUM")))

sres.des[,DAY:=TIME%/%24]
sres.des[,AUC.NMsim:=AUCNMSIM]
sres.auc.des=sres.des[AUCNMSIM!=0,.(TIME,DAY,PRED,AUC.NMsim)]

The plot comparing the DES and trapez AUC is obtained with the code below

sres.final=mergeCheck(sim.auc.trapez[,.(DAY,AUC,time.step)]
                     ,sres.auc.des[,.(DAY,AUC.NMsim)]
                     ,by="DAY")

ggplot(data=sres.final,aes(AUC.NMsim,AUC,colour=factor(time.step)))+
    geom_point(size=4)+
    labs(colour="Time step in fine grid")+
    scale_color_manual(values=c("orange", "blue", "darkgreen"))+
    xlim(c(0,17))+
    ylim(c(0,17))+
    ylab("AUC 0-24h by trapez method, on fine grid")+
    xlab("AUC 0-24h by integration through $DES, on coarse grid")+
    geom_abline(slope=1, intercept=0)
Daily exposures computed at run time ($DES, coarse grid, x-axis) and post-processing time (`trapez`, fine grids, y-axis). AUC (trapez) converges to the value computed with $DES method as the time step is reduced. Includes identity line.

Daily exposures computed at run time ($DES, coarse grid, x-axis) and post-processing time (trapez, fine grids, y-axis). AUC (trapez) converges to the value computed with $DES method as the time step is reduced. Includes identity line.