DRUG AND METABOLITE

From: bvatul@ufl.edu Subject: DRUG AND METABOLITE Date: Mon, 28 May 2001 09:39:06 -0400 Hello All Could somebody help me in this? I am analysing the sparse data of a drug and its metabolite after intravenous infusion. I first analysed the data of drug alone using ADVAN3 TRAN4. Using these parameters I then tried to fit the drug and metabolite simulatneously in ADVAN6 TRAN1. In the $DES I used only k10 (which is a sum of elimination of the parent drug and formation rate of its metabolite). I first simulated to get a good idea of starting parameters. I am getting better IPRED when I analyse the parent drug alone. But when I am analysing the drug and metabolite the IPRED of parent drug goes very bad. The variability in the data is also very high. My queries are as follows: 1. Does this show that I should fix the predetermined parameters of drug (ADVAN3)and float the metabolite parameters? 2. How will transformation of data (DV) help me? 3. In such cases which is the best method (FO or FOCE or FOCE with interaction). 4. Is it possible that similar distribution models do not apply for a drug and its metabolite in cases of high variability? How to recognise this? $PROBLEM ANALYSIS OF POP DATA $INPUT ... $DATA DM.CSV IGNORE=C; $SUBROUTINES ADVAN6 TRAN 1 TOL=3 $MODEL COMP=(1); CENTRAL) 1 COMP=(2); PERI) 2 COMP=(3); METAB) 3 COMP=(4); METAB 4 $PK TVQ=THETA(1) TVCL1=THETA(2) TVV1=THETA(3) TVV2=THETA(4) TVK13=THETA(5) TVK30=THETA(6) TVK34=THETA(7) TVK43=THETA(8) Q=TVQ*EXP(ETA(1)) CL1=TVCL1*EXP(ETA(2)) V1=TVV1*EXP(ETA(3)) V2=TVV2*EXP(ETA(4)) K13=TVK13*EXP(ETA(5)) K30=TVK30*EXP(ETA(6)) K34=TVK34*EXP(ETA(7)) K43=TVK43*EXP(ETA(8)) K12=Q/V1 K10=CL1/V1; K10=K10'+K13 K21=Q/V2 S1=V1/1000 S3=1 $DES DADT(1)=-K10*A(1)+K21*A(2)-K12*A(1) DADT(2)=K12*A(1)-K21*A(2) DADT(3)=K13*A(1)-K30*A(3)-K34*A(3)+K43*A(4) DADT(4)=K34*A(3)-K43*A(4) $THETA (0.00001, 47) ; Q (0.00001, 19.1) ; CL1 (0.00001, 11) ; V1 (57, FIX) ; V2 (0.00001, 2.96) ; K13 (0.00001, 0.18); k30 (0.00001, 0.3); k34 (0.00001, 0.1); K43 $OMEGA (0.181) (0.176) (0.5, FIX) (0.5) (0.5) (0.5) (0.5) (0.5) $ERROR Q1=0 IF(CMT.EQ.1)Q1=1 Q2=0 IF(CMT.EQ.3)Q2=1 Y1=F*(1+ERR(1))+ERR(3) Y2=F*(1+ERR(2))+ERR(4) Y=Q1*Y1+Q2*Y2 IPRED=F IRES=DV-IPRED $SIGMA (0.087) (0.1) (15.2) (10) $EST METHOD=0 MAXEVAL=9999 PRINT=5 NOABORT POSTHOC $TABLE .... Thanks in advance. Atul