Weight as Covariate

From: "Sreenivasa Rao Vanapalli" <rao@pharm.cpb.uokhsc.edu> Subject: Weight as Covariate Date: Fri, 22 Sep 2000 11:04:14 -0700 Dear NONMEM Users I'm working on bioavailability studies on different intranasal formulations using population approach in rats. Since the dose is fixed and during the study the weight of the aniaml is geetting larger, We decided to include weight as predictor for Vd. The structural model is two compartment with first order absorption. When we analyzed the data with NONMEM, We have two models: 1) without weight as covariate 2) with weight as covariate. I have obtained Bayesian individual estimates for parameters (Vd, K) using POSTHOC option with NONMEM. using this individual parameter estimates I have done exploratory data analysis for possible relationship between Vd and Weight. I found that there is a good relationship between Vd and weight. Interestingly when I include weight as covariate in my model minimum objective function (OBJ) decreased by 20 points. But the values of parameters changed so much that Ka and Vd values were decreased by a factor of 10 and K value was increased by a factor of 10. In other way it getting flip-flop. I am eager to know if anyone can explain this situation. (Is there anyway I can fix K value from prior knowledge). Here I'm attaching control files for both the models. (with weight as covariate) $PROBLEM PROMETHAZINE POOLED DATA $INPUT ID DOSE=AMT TIME CP=DV WT PROD EVID $DATA POOLEDATAWA $SUBROUTINES ADVAN4 $PK CALLFL=-1 KA1=THETA(1) KA2=THETA(2) KA3=THETA(3) K23=THETA(6)*EXP(ETA(1)) K32=THETA(7)*EXP(ETA(2)) K=THETA(8) TVVD=THETA(9)+THETA(10)*(WT-.3) V=TVVD*EXP(ETA(3)) S2=V KA=KA1 F1=1.0 IF (PROD.EQ.1) THEN F1=THETA(4) KA=KA2 ENDIF IF (PROD.EQ.2) THEN F1=THETA(5) KA=KA3 ENDIF $THETA (0,.15,10)(0,.4,10)(0,.35,10)(0,1.35,10)(0,1,10) (0,.035,10)(0,.045,100)(0,.008,1)(0,.1,100)(0,.9,10) $OMEGA .0001 .0001 .0001 $ERROR Y=F*(1+ERR(1))+ERR(2) $SIGMA .05 .001 $ESTIMATION MAXEVAL=9999 $COVARIANCE (without weight as covariate) $PROBLEM PROMETHAZINE POOLED DATA $INPUT ID DOSE=AMT TIME CP=DV WT PROD EVID $DATA POOLEDDATAW $SUBROUTINES ADVAN4 $PK CALLFL=-1 KA1=THETA(1) KA2=THETA(2) KA3=THETA(3) K23=THETA(6)*EXP(ETA(1)) K32=THETA(7)*EXP(ETA(2)) K=THETA(8) TVVD=THETA(9) V=TVVD*EXP(ETA(3)) S2=V KA=KA1 F1=1.0 IF (PROD.EQ.1) THEN F1=THETA(4) KA=KA2 ENDIF IF (PROD.EQ.2) THEN F1=THETA(5) KA=KA3 ENDIF $THETA (0,.15,10)(0,.4,10)(0,.35,10)(0,1.35,10)(0,1,10) (0,.035,10)(0,.045,100)(0,.008,10)(0,.9,100) $OMEGA .0001 .0001 .0001 $ERROR Y=F*(1+ERR(1))+ERR(2) $SIGMA .05 .001 $ESTIMATION MAXEVAL=9999 $COVARIANCE A part of data file 1 500 0 0 0.35 0 1 1 . 2 149 .35 0 0 1 . 30.9 262 .35 0 0 1 . 119 163 .35 0 0 1 500 0 0 0.245 1 4 1 . 2 451 .245 1 0 1 . 30 328 .245 1 0 1 . 120 147 .245 1 0 1 500 0 0 0.295 2 4 1 . 2.1 346 .295 2 0 1 . 29.4 332.7 .295 2 0 1 . 119.4 178.1 .295 2 0 (without weight as covariate) TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 TH 7 TH 8 TH 9 1.54E-01 4.07E-01 3.76E-01 1.35E+00 1.04E+00 3.51E-02 4.15E-02 8.29E-03 1.02E+00 (with weight as covariate) TH 1 TH 2 TH 3 TH 4 TH 5 TH 6 TH 7 TH 8 TH 9 TH10 3.39E-02 6.23E-02 6.28E-02 1.14E+00 9.34E-01 3.36E-01 3.20E-02 5.22E-02 1.33E-01 2.76E-01 With Regards Sreenivasa Rao Vanapalli College of Pharmacy,OUHSC 1110 N.Stonewall Oklahoma City, OK-73117 Tel:405-271-6484 Extn:47232 (office) :405-521-0826 (Home) Fax:405-271-7505(Office)