Autoinduction

From: "Sreenivasa Rao Vanapalli" <svanapal@blue.weeg.uiowa.edu> Subject: Autoinduction Date: Tue, 15 May 2001 19:24:51 -0500 hello NMUsers I'm trying to fit multiple oral data to a two compartment model. This drug has very long half life (20 days). Plasma samples were collected for 28 days for single dose and every 28 days for multiple dose for six doses and for twelve doses. Declined Plasma concentrations were observed after administration of second dose, suggesting autoinduction. I'm wondering if my control stream to model this data is right or wrong. Can someone help me out. I'm getting floating point error messages. $INPUT ID MDV DOSE=AMT TIME DV WT CMT SEX EVID $DATA MOXIMULTIEDIT $SUBROUTINES ADVAN8 TOL=5 $MODEL NCOMPARTMENTS=4 COMP=(DEPOT,INITIALOFF,DEFDOSE) COMP=(CENTRAL,DEFOBS,NOOFF) COMP=(PERIPH) COMP=(ENZ) $PK TVCLIN=THETA(1) CLIN=TVCLIN*EXP(ETA(1)) KA=THETA(2)*EXP(ETA(2)) K23=THETA(3)*EXP(ETA(3)) K32=THETA(4)*EXP(ETA(4)) TVVD=THETA(5) V=TVVD*EXP(ETA(5)) KENZ=THETA(6)*EXP(ETA(6)) IC50=THETA(7)*EXP(ETA(7)) S2=V $DES CP=A(2)/V C1=K23*A(2) C2=K32*A(3) CL=CLIN/A(4) DADT(1)=-KA*A(1) DADT(2)=KA*A(1)-C1+C2-CL*CP DADT(3)=C1-C2 DADT(4)=KENZ-KENZ*A(4)*(1-(CP/(CP+IC50))) $AESINITIAL IF (TIME.EQ.0)THEN A(4)=1 ENDIF $ERROR DEL=0 IF (F.EQ.0) DEL=1 W=F+DEL Y=F*(1+ERR(1))+ERR(2) IPRED=F IRES=DV-IPRED IWRES=IRES/W $THETA (0,.3,10) ;CLIN apparent drug clearance (0,.8,100) ;ABSOR (0,.1,10) ;K23 (0,.01,100) ;K32 (0,13,500);V (0,.001,100) ;KENZ rate constant for enzyme degradation/inactivation (0,200,1000) ;IC50 Drug conc at 50% of the max inhibition of enzyme degradation $OMEGA .002 .0001 .0001 .0001 .001 .001 .001 $SIGMA .05 .01 $ESTIMATION MAXEVAL=9999 POSTHOC $COVARIANCE Best regards Sreenivasa Rao Vanapalli, Ph.D, Janssen Postdoctoral Research Scholar, S411 PHAR, College of Pharmacy, University of Iowa, Iowa City, IA-52242 319-353-5157 (Office) 319-337-2687 (Home)