RE: Drug-metabolite kinetics

From: "Bachman, William" <bachmanw@globomax.com> Subject: RE: Drug-metabolite kinetics Date: Fri, 2 Jul 1999 15:21:19 -0400 One way to do this is to define a reasonable model using differential equations based on what you know about the drug and the metabolite. E.g., a one compartmental model for the parent and possibly interconversion of parent to metabolite (does metabolism occur in central compartment, is metabolism reversible?, does the metabolite also follow one compartment dispostion?) One then needs to define a CMT data item to specify which compartment the observation corresponds to (central for the parent, some other for the metabolite based on the metabolite portion of the structural model you are proposing.) Code might look something like this: $PROBLEM 1comp,rev.metab,both elim. 7/2/99 WJB $INPUT ID DOSE=AMT TIME DV CMT $DATA d:\vnmdata\TEST\TESTy.PRN IGNORE=C $SUBROUTINE ADVAN8 TRANS1 TOL=5 $MODEL NPAR=7 NCOMP=3 COMP=(DEPOT,DEFDOSE) COMP=(PARENT) COMP=(METAB) $PK KA= THETA(1) ;KA VP= THETA(2) ;VP central vol. parent CL= THETA(3) ;CL clearance parent VMT=THETA(4) ;VMT central vol. metab KF= THETA(5) ;KF parent->metab. conversion KB= THETA(6) ;KB metab.->parent conversion CLM=THETA(7) ;CLM clearance metab. S2=VP ;SCALING FACTOR FOR PARENT IN CENTRAL COMP S3=VMT ;SCALING FACTOR FOR METAB. IN CENTRAL COMP $DES DADT(1)=-KA*A(1) DADT(2)=KA*A(1)-KF*A(2)+KB*A(3)-CL*A(2)/VP DADT(3)=KF*A(2)-KB*A(3)-CLM*A(3)/VMT $ERROR W1=1 W2=F IPRED=F IRES=DV-IPRED IWRES=IRES/(W1+W2) Y=F + W1*ERR(1) + W2*ERR(2) $THETA (0,2.5) ;1 KA $THETA (0,35) ;2 VP $THETA (0,0.75) ;3 CL $THETA (0,15) ;4 VMT $THETA (0,0.1) ;5 KF $THETA (0,0.05) ;6 KB $THETA (0,2.0) ;7 CLM $OMEGA (1)(0.1) $ESTIMATION PRINT=5 MAXEVAL=9999 $TABLE ID TIME CMT NOPRINT FILE=TESTy.PAR Code not guaranteed to be 100% error free, but, it will give you a starting point. note: this is coded for individual dated, add etas for population data. hope this helps, Bill William J. Bachman, Ph.D. GloboMax LLC Senior Scientist 7250 Parkway Drive, Suite 430 Hanover, MD 21076 Voice (410) 782-2212 FAX (410) 712-0737 bachmanw@globomax.com