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