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

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