RE: Simultaneous drug and metabolite POPPK

Dear Vijai, An example of a model fitted to log-transformed plasma concentrations of a parent drug and its active metabolite (cf. extended model in European Journal of Clinical Pharmacology 2002;58(4) Suppl:S1-S67.): Program code: $PROBLEM Parent drug & active metabolite $INPUT ID AMT TIME RATE EVID CMT DV $DATA XXXXX.prn IGNORE=# $SUBROUTINES ADVAN5 $MODEL COMP=(DEFOBS1); central compartment of parent drug COMP=(PERIPH1); peripheral compartment of parent drug COMP=(PERIPH2); peripheral compartment of parent drug COMP=(DEFOBS2); central compartment of metabolite COMP=(PERIPH3); peripheral compartment of parent drug COMP=(PERIPH4); peripheral compartment of parent drug COMP=(PERIPH5); compartment of intermediary metabolites between parent drug and active metabolite $PK ;---------------------------------------------------------------------------- ;BASIC PK OF PARENT DRUG (observations after two intravenous infusions given 12 h apart) ;---------------------------------------------------------------------------- K10=THETA(1)*(1+ETA(1)) K12=THETA(2)*(1+ETA(2)) K21=THETA(3)*(1+ETA(3)) K13=THETA(4)*(1+ETA(4)) K31=THETA(5)*(1+ETA(5)) ;---------------------------------------------------------------------------- ;BASIC PK OF ACTIVE METABOLITE (observations after two intravenous infusions given 12 h apart or after two intravenous infusions of the parent drug given 12 h apart) ;---------------------------------------------------------------------------- K40=THETA(6)*(1+ETA(6)) K45=THETA(7)*(1+ETA(7)) K54=THETA(8)*(1+ETA(8)) K46=THETA(9)*(1+ETA(9)) K64=THETA(10)*(1+ETA(10)) ;---------------------------------------------------------------------------- ;VOLUMES OF DISTRIBUTION ;---------------------------------------------------------------------------- S1 =THETA(11)*(1+ETA(11)) S4 =THETA(11)*(1+ETA(11)); joint estimate for parent drug and active metabolite ;---------------------------------------------------------------------------- ;SYSTEMIC GENERATION OF ACTIVE METABOLITE ;---------------------------------------------------------------------------- K74=THETA(12)*(1+ETA(12)); transformation of intermediary to active metabolite K17=THETA(13)*(1+ETA(13)); transformation of parent drug to intermediary metabolite ;---------------------------------------------------------------------------- $ERROR IF (EVID.EQ.0.AND.F.GT.0) THEN IPRED=LOG(F) ELSE IPRED=LOG(F+1) ENDIF IRES=DV-IPRED IWRES=IRES X1=0 X2=0 IF(CMT.EQ.1)X1=1; flag for parent drug observation(CMT=1) IF(CMT.EQ.4)X2=1; flag for active metabolite observation(CMT=4) Y=IPRED+X1*EPS(1)+X2*EPS(2) ..... Data file XXXX.prn, first subject # ID AMT TIME RATE EVID CMT DV 1 2214 0 27675 4 1 XXX 1 . 0.08 . 0 1 XXX 1 . 0.25 . 0 1 XXX 1 . 0.5 . 0 1 XXX 1 . 0.999 . 0 1 XXX 1 . 0.999 . 0 4 YYY 1 2208 1 27600 1 1 . 1 . 1.08 . 0 1 XXX 1 . 1.08 . 0 4 YYY 1 . 1.25 . 0 1 XXX 1 . 1.25 . 0 4 YYY 1 . 1.5 . 0 1 XXX 1 . 1.5 . 0 4 YYY 1 . 2 . 0 1 XXX 1 . 2 . 0 4 YYY 1 . 2.5 . 0 1 XXX 1 . 2.5 . 0 4 YYY 1 . 3 . 0 1 XXX 1 . 3 . 0 4 YYY 1 . 4 . 0 1 XXX 1 . 4 . 0 4 YYY 1 . 6 . 0 4 YYY 1 . 8 . 0 1 XXX 1 . 8 . 0 4 YYY 1 . 9 . 0 4 YYY 1 . 12 . 0 4 YYY 1 . 15 . 0 1 XXX 1 . 15 . 0 4 YYY 1 . 21 . 0 4 YYY 1 . 43 . 0 4 YYY 1 756 0 9450 4 4 . 1 . 0.08 . 0 4 YYY 1 . 0.25 . 0 4 YYY 1 . 0.5 . 0 4 YYY 1 . 0.999 . 0 4 YYY 1 762 1 9525 1 4 . 1 . 1.08 . 0 4 YYY 1 . 1.25 . 0 4 YYY 1 . 1.5 . 0 4 YYY 1 . 2 . 0 4 YYY 1 . 2.5 . 0 4 YYY 1 . 3 . 0 4 YYY 1 . 4 . 0 4 YYY 1 . 8 . 0 4 YYY 1 . 15 . 0 4 YYY 1 . 21 . 0 4 YYY 1 . 31 . 0 4 YYY / Johan > Johan Rosenborg > Senior Pharmacokineticist, Clinical Pharmacology > Medical Science Sweden > AstraZeneca R&D Lund > SE-221 87 Lund, Sweden Tel: +46 46 33 65 99