$Simulation using random post-dose times

Title: Paul R Colleagues: I am trying to simulate a population PKPD data set to guide a clinical trial. I plan to obtain weekly or biweekly samples (a single time PK with corresponding BP measurement each) over the last 4 months of pregnancy. I hope to model BOV over the final weeks of pregnancy as well, but other covariates will be tested in the actual clinical trial. My expectation is that the subjects will present to clinic at varying times after their last dose of antihypertensive, and I don't want to bet on them remembering to bring their dose to clinic for a witnessed dose and subsequent, timed sample. I don't know how to fit the simulation using random time points after their last steady-state dosing event except by sending the simulated data to a file with ONLYSIMULATION, then selecting random sample times from this data set with R, writing it to a new data file, and modeling that data set with NONMEM. My question is this: Can anyone suggest a way to have NONMEM itself calculate a concentration at a random time during a dosing interval, so that within the same model a corresponding effect can be modeled? ctl stream follows... $PROBLEM LABETALOL $INPUT ID TIME AMT DV DVID EVID $DATA ..\LABETALOL_PKPDSIM2.CSV IGNORE=# $SUBROUTINES ADVAN6 TOL=3 $MODEL NCOMP=2 NPAR=6 COMP=(GUT, DEFDOSE) COMP=(CENTRAL) $SIMULATE (12345) SUBPROBLEMS=10; (higher SUBP to come) $PK ;PK TVKA=kas KA=TVKA * EXP(ETA(1)) TVCL = clf CL= TVCL * EXP(ETA(2)) TVV = vcf V=TVV * EXP(ETA(3)) S2=V/1000 K=CL/V ;PD SLOP = slp * EXP(ETA(4)) INTR = int * EXP(ETA(5)) $DES DADT(1) = -A(1)*KA DADT(2) = A(1)*KA - A(2)*K $ERROR IPRE = F W1=F DEL = 0 IF(IPRE.LT.0.001) DEL = 1 IRES = DV-IPRE; NEGATIVE TREND IS OVERESTIMATING IPRED WRT DV IWRE = IRES/(W1+DEL) Y1=0 Y2=0 IF(DVID.EQ.1) Y1=F*(1+ERR(1)); DV = concentration IF (DVID.EQ.2) THEN Y2=(SLOP*A(2)+INTR)*(1+ERR(2)); DV = change in BP ENDIF Y=Y1+Y2 $THETA (2.98 FIXED); kas $THETA (246 FIXED); clf $THETA (714 FIXED); vcf ;EFFECT $THETA (0,0.05); SLP $THETA (0,1); INT $OMEGA 0.05; ivka $OMEGA 0.05; ivcl $OMEGA 0.05; ivv $OMEGA 0.01; ivin $OMEGA 0.005; ivsl $SIGMA 0.03; sig1 $SIGMA 0.03; sig2 $ESTIMATION METH=1 INT SIGDIGITS=3 MAXEVAL=9999 PRINT=10 NOABORT ;DEFINE TABLES FOR XPOSE $TABLE ID KA CL V SLOP INTR NOPRINT FIRSTONLY NOHEADER FILE=PATAB1 $TABLE ID TIME DVID IPRE IRES IWRE NOPRINT ONEHEADER FILE=SDTAB1 -- Paul R. Hutson, Pharm.D. Associate Professor UW School of Pharmacy 777 Highland Avenue Madison WI 53705-2222 Tel 608.263.2496 Fax 608.265.5421 Pager 608.265.7000, p7856