Weibull Absorption Simulation - Multiple Doses
Dear NMUsers,
I recently modeled some single dose oral data in NONMEM, in which a 2
compartment Weibull absorption model described the data best. Now I'm trying to
simulate either QD or BID dosing to obtain predicted Ct profiles on Day 8. For
some reason the simulation doesn't acknowledge any dosing past the first dose
at time 0, despite doses being present in the data file. I think it has
something to do with $DES, and not specifying doses and dose times in the
control stream. See below for my control stream. I found a message thread in
the archive with some advice on this from Nick Holford
( http://www.cognigencorp.com/nonmem/current/2007-April/0094.html) but even
after implementing his suggestion, I still cannot successfully simulate
multiple dosing. Any help or insight would be appreciated. Thanks.
Burgess Freeman, Pharm.D.
Sr. Research Scientist
Drug Metabolism, Pharmacokinetics & Clinical Pharmacology (DMPKCP)
Array BioPharma, Inc.
Boulder, CO 80301
$PROBLEM run4.mod - SIMULATION 2COMPWB T, IIV+PROP, FOCE-I w g95
; http://www.cognigencorp.com/nonmem/current/2007-April/0094.html
$INPUT ID TIME DV AMT CMT EVID MDV GRP
$DATA sim.csv IGNORE #
$SUBROUTINES ADVAN6 TOL=4
$MODEL NCOMP=3
COMP=(DEPOT,DEFDOSE) COMP=(CENTRAL,DEFOBS) COMP=(PERHIPH)
$PK
TCL=THETA(1)
TV2=THETA(2)
TQ=THETA(3)
TV3=THETA(4)
;Weibull parameters
TBETA=THETA(5)
TALPHA=THETA(6)
CL=TCL*EXP(ETA(1))
IF (ABS(ETA(1)).GT.100.) EXIT 1 100
V2=TV2*EXP(ETA(2))
IF (ABS(ETA(2)).GT.100.) EXIT 1 200
Q=TQ*EXP(ETA(3))
IF (ABS(ETA(3)).GT.100.) EXIT 1 300
V3=TV3*EXP(ETA(4))
IF (ABS(ETA(4)).GT.100.) EXIT 1 400
BETA=TBETA*EXP(ETA(5))
IF (ABS(ETA(5)).GT.100.) EXIT 1 500
ALPHA=TALPHA*EXP(ETA(6))
IF (ABS(ETA(6)).GT.100.) EXIT 1 600
S2=V2
S3=V3
K20=CL/V2
K23=Q/V2
K32=Q/V3
$DES
DADT(1)=-A(1)*(BETA/ALPHA)*((T/ALPHA)**(BETA-1))*EXP(-(T/ALPHA)**BETA)
DADT(2)=-DADT(1)-K20*A(2)-K23*A(2)+K32*A(3)
DADT(3)=K23*A(2)-K32*A(3)
$THETA
6.6
25.3
0.266
6.38
4.1
3.09
$ERROR
;Proportional Error
Y=F*(1.0+ERR(1))
IPRED=F
IRES=DV-IPRED
IWRES=IRES/IPRED
$SIGMA 0.207
$OMEGA 0.068 0.00409 0.00002 0.0701 0.00936 0.181
$SIMULATION (123456789) ONLYSIM
$TABLE ID CL V2 Q V3 ALPHA BETA K20 K23 K32 ETA1 ETA2 ETA3 ETA4 ETA5 ETA6
NOPRINT ONEHEADER FILE=patab4
$TABLE ID TIME DV MDV PRED IPRED IWRES RES WRES IRES GRP
NOPRINT ONEHEADER FILE=sdtab4
$TABLE ID GRP
NOPRINT ONEHEADER FILE=cotab4
$TABLE ID GRP
NOPRINT ONEHEADER FILE=catab4