Autoinduction

From: "Sreenivasa Rao Vanapalli" <svanapal@blue.weeg.uiowa.edu> Subject: Autoinduction Date: Mon, 14 May 2001 17:33:55 -0500 Dear NMUsers I'm trying to fit multiple oral dose data with autoinduction. The data fits well to a two compartment model with first order absorption. But when I'm trying to fit the data to a two compartment with hypothetical enzyme compartment, I'm getting error message 'floating-point error:divide by zero' The control file I'm using is, $PROBLEM MOXIDECTIN POOLED DATA $INPUT ID DOSE=AMT TIME CP=DV WT CMT SEX EVID $DATA MOXIMULTIEDIT $SUBROUTINES ADVAN6 TOL=5 $MODEL NCOMPARTMENTS=4 COMP=(DEPOT,INITIALOFF,DEFDOSE) COMP=(CENTRAL,DEFOBS,NOOFF) COMP=(ENZ) COMP=(PERIPH) $PK TVCLIN=THETA(1) CLIN=TVCLIN*EXP(ETA(1)) KA=THETA(2)*EXP(ETA(2)) Q=THETA(3)*EXP(ETA(3)) TVVD=THETA(4) V2=TVVD*EXP(ETA(4)) V3=THETA(5)*EXP(ETA(5)) KENZ=THETA(6)*EXP(ETA(6)) IC50=THETA(7)*EXP(ETA(7)) $DES DADT(1)=-KA*A(1) DADT(2)=KA*A(1)-CLIN*DV DADT(3)=KENZ-KENZ*A(3)*(1-(CP/(CP+IC50))) $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 CL=CLIN/A(3) $THETA (0,.3,10) ;CLIN (0,.8,100) ;ABSOR (0,1.5,10) ;Q (0,13,100) ;V2 (0,100,500);V3 (0,.001,100) ;KENZ (0,500,1000) ;IC50 $OMEGA .002 .0001 .0001 .0001 .001 .001 .001 $SIGMA .05 .01 $ESTIMATION MAXEVAL=9999 POSTHOC $COVARIANCE $TABLE ID WT TIME V2 CL KA $SCAT CP VS TIME $SCAT PRED VS TIME $SCAT (RES WRES) VS TIME $SCAT WRES VS CP UNIT $SCAT PRED VS CP UNIT Any help would be appreciated. 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)

From: "Piotrovskij, Vladimir [JanBe]" <VPIOTROV@janbe.jnj.com> Subject: RE: Autoinduction Date: Tue, 15 May 2001 09:00:19 +0200 Sreenivasa, Very short look at your code: you have 3 diff eqs in the $DES block, but 4 compartments are declaired in the $MODEL block. Best regards, Vladimir

From: "Ziad Hussein" <zhussein@medeval.com> Subject: RE: Autoinduction Date: Tue, 15 May 2001 09:32:58 +0100 Dear Sreenivasa, Few years ago I have used a model with autoinduction for lamotrigine without the use of differential equation British Journal of Clinical Pharmacology 43: 457-465, 1997. The equation to describe autoinduction is: TVCL=Theta(1)-Theta(2)*exp(-Theta(3)*Time) in our case lamotrigine was dosed over 48 weeks. I hope that your data covers at least 2 weeks of dosing to able to model the autoinduction. Kind regards, Dr Ziad Hussein Head of Pharmacokinetics Medeval Ltd Skelton House Manchester Science Park Lloyd Street North Manchester, UK Tel: xx-44-161-226 6525 (Ext 295)

From: "Gibiansky, Ekaterina" <gibianskye@globomax.com> Subject: RE: Autoinduction Date: Tue, 15 May 2001 13:24:43 -0400 Sreenivasa, another short look. You should not use observed values (DV, CP) in the $DES block, differential equations should be written in terms of predicted amounts in the compartments (A(2)/V2 in your case). Also, equation 3 does not seem right. Regards, Katya -------------------------------------------------- Ekaterina Gibiansky, PhD Senior Scientist GloboMax LLC 7250 Parkway Drive, Suite 430 Hanover, MD 21076 Voice (410) 782-2234 FAX (410) 712-0737 E-mail: gibianskye@globomax.com

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)

From: "Piotrovskij, Vladimir [JanBe]" <VPIOTROV@janbe.jnj.com> Subject: RE: Autoinduction Date: Wed, 16 May 2001 08:48:37 +0200 Sreenivasa, You modified already your control compared to the yesterday version, particularly, you excluded DV from $DES block. There are still a few issues that may cause problems: 1. An enzyme submodel. I prezume the enzyme should have some steady-state level which is altered by the drug. There should be a formation rate for the enzyme not equal to KENZ, say KIN. The baseline amount of enzyme is then KIN/KENZ. 2. Initialization of compartment 4. I think you do not need $AESINITIAL. You have to introduce a unit amount into COMP 4 at TIME=0 using an extra dose record in your data set. 3. In your model, the enzyme has no impact on the drug elimination. In the framework of the autoinduction model CL should depend on the enzyme amount. Have a look at the following recent publications: 1. Hassan M. Svensson USH. Ljungman P. Bjorkstrand B. Olsson H. Bielenstein M. Abdel-Rehim M. Nilsson C. Johansson M. Karlsson MO. A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients. British Journal of Clinical Pharmacology. 1999; 48(5):669-677. 2. Kerbusch T. Huitema ADR. Ouwerkerk J. Keizer HJ. Mathot RAA. Schellens JHM. Beijnen JH. Evaluation of the autoinduction of ifosfamide metabolism by a population pharmacokinetic approach using NONMEM. British Journal of Clinical Pharmacology. 2000; 49(6):555-561. Best regards, Vladimir