NONMEM Users Network Archive

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Weibull Absorption Simulation - Multiple Doses

From: Freeman, Burgess <Burgess.Freeman>
Date: Sat, 24 Apr 2010 19:04:16 -0600

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

 
Received on Sat Apr 24 2010 - 21:04:16 EDT

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