THETA: 1)K13 2)K23 3)DURATION 4)LAG 5)LOGIT 6)K30 7)K34 8)VOLUME 9)K1315 10)K1415 11)DURATION 12)LAG 13)LOGIT 14)K150 15)K1516 16)VOLUME 17)WT 18)WT ETA: 19) 20) 21) 22) 23) 24) 25) ERR: TEST1.lst -2681.582 FOCEI eval=524 sig=3.2 sub=34 obs=1154 NM7.3.0 PP7.3.0 THETA = 3.22 2.18 0.9 10 -0.75 3.92 1.29 3000 0.273 0.0861 0.9 10 -0.75 43.9 1.29 3000 0.5 0.5 ETASD = 0.671c 0.640c 0.947 0.126c 0.447c 0.000 0.305 ETAPval = 0.199 0.036 0.189 0.000 0.000 0.207 0.008 ETAshr% = 35.3 36.3 20.7 31.0 58.4 99.9 0.8 EBVshr% = 16.3 10.9 11.0 30.6 19.4 99.9 2.1 EPSshr% = 100.0 8.0 8.0 EPSSD = 0.707c 0.500 0.018 MINIMIZATION SUCCESSFUL HOWEVER, PROBLEMS OCCURRED WITH THE MINIMIZATION. REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM ONLY AFTER CHECKING THAT THE COVARIANCE STEP PRODUCES REASONABLE OUTPUT. Ttot 587:27.61 Test 587:22.08 Tcov 0:0 Ttcl 0:5.53 $PROBLEM PHYSIOLOGICAL MODEL L CHANGED EQ FOR ARTERIAL $DATA ..\CONPHYDAT1.CSV IGNORE=C $INPUT DROP TIME CMT DV DROP AMT=DOSE EVID MDV RATE SEX WT ID $SUBR ADVAN13 TRANS1 TOL=4 ;1 FIX etas for ka's F met Lag ;2 FIX etas for ka's F oral Lag ;3 FIX etas for ka's met oral Lag, remove UL on Ka values ;4 FIX etas for ka's met oral F ;6 FIX etas for ka's lag oral no UL on ka ;8 New initial estimates based upon fit 6 ;8e Fix F $MODEL ;D MODEL COMPARTMENTS COMP=(1);D (ABSORB,DEFDOSE); DOSE STOMACH FAST ABS COMP=(2);D (ABSORB,DEFDOSE); DOSE STOMACH SLOW ABS COMP=(3); SMALL INT_D COMP=(4); LIVER_D COMP=(5); HEART_D COMP=(6); GONADS_D COMP=(7); SLOWLY PERFUSED_D COMP=(8); RICHLY PERFUSED_D COMP=(9); BRAIN_D COMP=(10); FAT_D COMP=(11); VENOUS_D COMP=(12); ARTERY_D ;L MODEL COMPARTMENTS COMP=(13);L (ABSORB,DEFDOSE); DOSE STOMACH FAST ABS COMP=(14);L (ABSORB,DEFDOSE); DOSE STOMACH SLOW ABS COMP=(15); SMALL INT_L COMP=(16); LIVER_L COMP=(17); HEART_L COMP=(18); GONADS_L COMP=(19); SLOWLY PERFUSED_L COMP=(20); RICHLY PERFUSED_L COMP=(21); BRAIN_L COMP=(22); FAT_L COMP=(23); VENOUS_L COMP=(24); ARTERY_L $PK "FIRST " USE PRDATA, ONLY: MXSTP01 " MXSTP01=5000 ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; ;SCALED FRACTIONAL TISSUE VOLUMES SAME FOR TEST AND REFERENCE ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; SBW=75 ;1)KG VLV=0.026*WT ;2)FRACTIONAL VOLUME OF LIVER IF(SEX.EQ.1) THEN VHR=0.0045*WT ;3)MALE FR VOLUME HEART ELSE VHR=0.0042*WT ;4)FEMALE FR VOLUME HEART ENDIF IF(SEX.EQ.1) THEN VGN=0.0007*WT ;5)MALE FR VOLUME GONADS ELSE VGN=0.0027*WT ;6)FEMALE FR VOLUME GONADS ENDIF IF(SEX.EQ.1) THEN VFT=0.213*WT ;7)MALE VOLUME FAT ELSE VFT=0.327*WT ;8)FEMALE VOLUME FAT ENDIF VBR=0.02*WT ;9)VOLUME BRAIN VPL=0.0435*WT ;10)FRACTIONAL VOLUME OF PLASMA ;SLOW PERFUSION IF(SEX.EQ.1) THEN VSL=(0.60-0.213-0.0045)*WT ;11)MALE VOLUME SLOW ELSE VSL=(0.60-0.327-0.0042)*WT ;12)FEMALE VOLUME SLOW ENDIF ;RICH PERFUSION IF(SEX.EQ.1) THEN VRI=(0.33-0.026+0.0435+0.0007+0.02)*WT ;13)MALE VOLUME RICH ELSE VRI=(0.33-0.026+0.0435+0.0027+0.02)*WT ;14)FEMALE VOLUME RICH ENDIF ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; ;SCALED PHYSIOL BLOOD FLOW VALUES SAME FOR TEST AND REFERENCE ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; QCO=15.87*(WT)**0.75 ;1)CARDIAC OUTPUT QLV=0.24*QCO ;2)FLOW TO LIVER IF(SEX.EQ.1) THEN QHR=0.038*WT ;3)FLOW TO HEART MALE ELSE QHR=0.047*WT ;4)FLOW TO HEART FEMALE ENDIF IF(SEX.EQ.1) THEN QGN=0.00054*WT ;5)FLOW TO GONADS MALE ELSE QGN=0.00022*WT ;6)FLOW TO GONADS FEMALE ENDIF IF(SEX.EQ.1) THEN QFT=0.053*WT ;7)FLOW TO FAT MALE ELSE QFT=0.091*WT ;8)FLOW TO FAT FEMALE ENDIF QBR=0.11*QCO ;10) FLOW TO BRAIN ;SLOW PERFUSION IF(SEX.EQ.1) THEN QSL=(0.24-0.053-0.038)*QCO ;11)FLOW MALE ELSE QSL=(0.24-0.091-0.047)*QCO ;12)FLOW FEMALE ENDIF ;RAPID PERFUSION IF(SEX.EQ.1) THEN QRI=(0.76-0.24-0.00054-0.11)*QCO ;13)FLOW MALE ELSE QRI=(0.76-0.24-0.00022-0.11)*QCO ;14)FLOW FEMALE ENDIF ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; ;PARTITION COEFFICIENTS FOR METHYLPHENIDATE SAME ;FOR TEST AND REFERENCE ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; PLV=5.66 ;1)PARTITION FOR LIVER PFT=1.79 ;2)PARTITION FAT PRI=6.07 ;3) PARTITION RICH PSL=2.47 ;4) PARTITION SLOW PGN=3.12 ;5) PARTITION GONADS PHR=2.19 ;6) PARTITION HEART PBR=6.07 ;7) PARTITION BRAIN ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; ;SCALED KINETIC PARAMETERS SAME FOR TEST AND REFERENCE ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; ;GUT D FAST ABS ZERO ORDER COMP1 MU_1=LOG(THETA(1))-0.25*LOG(WT) ;1)FAST ZERO ORDER MG/H K13=EXP(MU_1+ETA(1)) MU_2=LOG(THETA(2))-0.25*LOG(WT) ;2)SLOW IST ORDER 1/H K23=EXP(MU_2+ETA(2)) MU_3=LOG(THETA(3))-0.25*LOG(WT) ;3)DUR FOR ABS COMP1 (F1K0*AMT)HR D1=EXP(MU_3+ETA(3)) MU_4=LOG(THETA(4))-0.25*LOG(WT) ;4)LAG ON SLOW COMP HR TLAG2=EXP(MU_4+ETA(4)) ALAG2=(D1+TLAG2) ;TOTAL LAG TIME ON COMP 2 MU_5=THETA(5) ;5)AVAILABILITY LOGITD=MU_5 TVF1=1/(1+EXP(-LOGITD+ETA(5))) F1=TVF1 F2=1-F1 MU_6=LOG(THETA(6))-0.25*LOG(WT) ;6)MET GUT 1/H K30=EXP(MU_6+ETA(6)) MU_7=LOG(THETA(7))-0.25*LOG(WT) ;7)ORAL UPTAKE_D 1/H K3L K34=EXP(MU_7+ETA(7)) MU_8=LOG(THETA(8)) ;8) VOLUME V11=EXP(MU_8) S11=V11/1 ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; ;GUT L FAST ABS ZERO ORDER COMP13 ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; MU_9=LOG(THETA(9))-0.25*LOG(WT) ;FAST ZERO ORDER MG/H K1315=EXP(MU_9) MU_10=LOG(THETA(10))-0.25*LOG(WT) ;SLOW IST ORDER 1/H K1415=EXP(MU_10) MU_11=LOG(THETA(11))-0.25*LOG(WT) ;DUR FOR ABS COMP1 (F1K0*AMT)HR D13=EXP(MU_11) MU_12=LOG(THETA(12))-0.25*LOG(WT) ;LAG ON SLOW COMP HR TLAG14=EXP(MU_12) ALAG14=(D13+TLAG14) ;TOTAL LAG TIME ON COMP 2 MU_13=THETA(13) ;AVAILABILITY LOGITL=EXP(MU_13) TVF13=1/(1+EXP(-LOGITL)) F13=TVF13 F14=1-F13 MU_14=LOG(THETA(14))-0.25*LOG(WT) ;5)MET GUT 1/H K150=EXP(MU_14) MU_15=LOG(THETA(15))-0.25*LOG(WT) ;6)ORAL UPTAKE_L 1/H K3L K1516=EXP(MU_15) ;LIVER D OXIDATION KMETD=0.7*(WT**0.75) ;CL DMPH OXID,L/H ;LIVER D HYDROLYSIS KMD=27600 ;KMLIV_D UG/L KML=10172 ;KMLIV_L UG/L VMD=38000*(WT**0.75) ;VMAX_D UG/H(UG/H/KG*KG) ;LIVER L OXIDATION KMETL=0.7*(WT**0.75) ;CL LMPH OXID,L/H ;LIVER L HYDROLYSIS VML=90000*(WT**0.75) ;VMAX_L UG/H ;@1HR MU_16=LOG(THETA(16)) V23=EXP(MU_16) S23=V23/1 ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; ;DIFFERENTIAL EQUATIONS. SHOULD INCLUDE ALL DYNAMICALLY CHANGING COMPONENTS, INCLDUE A(), AND THEIR DEPENDENCIES ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; $DES ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; ;VENOUS D CONCENTRATIONS BASED UPON PARTITION ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; CDLV=A(4)/(PLV*VLV) ;1)CONC_D VENOUS LIVER UG/L CDHR=A(5)/(PHR*VHR) ;2)CONC_D HEART CDGO=A(6)/(PGN*VGN) ;3)CONC_D GONADS CDSL=A(7)/(PSL*VSL) ;5) CONC_D SLOW CDRI=A(8)/(PRI*VRI) ;6) CONC_D RICH CDBR=A(9)/(PBR*VBR) ;7) CONC_D BRAIN CDFT=A(10)/(PFT*VFT) ;8) CONC_D FAT AD=(CDBR*QBR+CDFT*QFT) CVD=((CDLV*QLV+CDHR*QHR+CDGO*QGN+CDSL*QSL+CDRI*QRI+AD)/QCO) ;CONC_D VENOUS PLASMA UG/L CAD=A(12)/VPL ;CONC_D ART PLASMA UG/L ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; ;VENOUS L CONCENTRATIONS BASED UPON PARTITION ;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;;; CLLV=A(16)/(PLV*VLV) ;1)CONC_L VENOUS LIVER UG/L CLHR=A(17)/(PHR*VHR) ;2)CONC_L HEART CLGO=A(18)/(PGN*VGN) ;3)CONC_L GONADS CLSL=A(19)/(PSL*VSL) ;5) CONC_L SLOW CLRI=A(20)/(PRI*VRI) ;6) CONC_L RICH CLBR=A(21)/(PBR*VBR) ;7) CONC_L BRAIN CLFT=A(22)/(PFT*VFT) ;8) CONC_L FAT AL=(CLBR*QBR+CLFT*QFT) CVL=((CLLV*QLV+CLHR*QHR+CLGO*QGN+CLSL*QSL+CLRI*QRI+AL)/QCO) ;CONC_L VENOUS PLASMA UG/L CAL=A(24)/VPL ;CONC_L ART PLASMA UG/L ;DYNAMIC COMPONENT EQUATIONS D AND L RHYD=VMD*CDLV/(KMD*(1+(CLLV/KML))+CDLV);HYDROLYSISD RATE UG/H RHYL=VML*CLLV/(KML*(1+(CDLV/KMD))+CLLV);HYDROLYSISL RATE UG/H RMETD=(KMETD*CDLV) ;RATE DMPH OXID,UG/H RMETL=(KMETL*CLLV) ;RATE LMPH OXID,UG/H ;D DIFFE DADT(1)=-A(1)*K13 ;1)GUTD FAST ABS TO INT DADT(2)=-A(2)*K23 ;2)GUTD SLOW ABS TO INT DADT(3)=A(1)*K13+A(2)*K23-A(3)*K30 ;3)ABS AND GUT METAB DADT(4)=QLV*(CAD-CDLV)+A(3)*K34-RHYD-RMETD ;4)D LIVER DADT(5)=QHR*(CAD-CDHR) ;5)D HEART DADT(6)=QGN*(CAD-CDGO) ;6)D GONADS DADT(7)=QSL*(CAD-CDSL) ;7)D SLOWLY PER DADT(8)=QRI*(CAD-CDRI) ;8)D RICHLY PER DADT(9)=QBR*(CAD-CDBR) ;9)D BRAIN DADT(10)=QFT*(CAD-CDFT) ;10) D FAT DADT(11)=QCO*(CVD-CAD) ;11)PLASMA D DADT(12)=QCO*(CVD-CAD) ;12)D ARTERY ;L DIFFE DADT(13)=-A(13)*K1315 ;13)GUTL FAST ABSTO INT DADT(14)=-A(14)*K1415 ;14)GUTL SLOW ABS TO INT DADT(15)=A(13)*K1315+A(14)*K1415-A(15)*K150 ;15)ABS AND GUT METAB DADT(16)=QLV*(CAL-CLLV)+A(15)*K1516-RHYL-RMETL ;16)L LIVER DADT(17)=QHR*(CAL-CLHR) ;17)L HEART DADT(18)=QGN*(CAL-CLGO) ;18)L GONADS DADT(19)=QSL*(CAL-CLSL) ;19)L SLOWLY PER DADT(20)=QRI*(CAL-CLRI) ;20)L RICHLY PER DADT(21)=QBR*(CAL-CLBR) ;21)L BRAIN DADT(22)=QFT*(CAL-CLFT) ;22) L FAT DADT(23)=QCO*(CVL-CAL) ;23)PLASMA L DADT(24)=QCO*(CVL-CAL) ;24)L ARTERY ;D THETA VALUES $THETA (0.1 4.67 ) ;1)K13 FAST STOMACH TO SMALL INT D $THETA (0.01 2.16 ) ;2)K23 SLOW STOMACH TO SMALL INT D $THETA 0.9 FIX ;3)DURATION TO ABSORB D HR $THETA 10 FIX ;4)LAG ON SLOW COMP 2 FOR D HR $THETA -0.75 FIX ;5)LOGIT D $THETA (0.04 3.2 ) ;6)K30 GUT METAB D $THETA 1.29 FIX ;7)K34 ORAL ABSORPTION D FIX $THETA 3000 FIX ;8)VOLUME D PLASMA ML ;L THETA VALUES $THETA (0.05 0.9) ;9)K1315 FAST STOMACH TO SMALL INT L $THETA (0.01 0.5) ;10)K1415 SLOW STOMACH TO SMALL INT L $THETA 0.9 FIX ;11)DURATION TO ABSORB L HR $THETA 10 FIX ;12)LAG ON SLOW COMP FOR L HR $THETA -0.75 FIX ;13)LOGIT L $THETA (1.46 10 ) ;14)K150 GUT METAB L $THETA 1.29 FIX ;15)K1516 ORAL ABSORPTION L ; VOLUME L $THETA 3000 FIX ;16)VOLUME L PLASMA ML ;WEIGHTS $THETA 0.5 FIX ;17)WT FOR D $THETA 0.5 FIX ;18)WT FOR L ;D VARIANCES $OMEGA 0.45 FIX ;19) FAST ZERO ORDER $OMEGA 0.41 FIX ;20) SLOW FIRST ORDER $OMEGA 0.2 ;21) DURATION OF ZERO ORDER $OMEGA 0.016 FIX ;22) LAG ON 2 $OMEGA 0.2 FIX ;23) AVAIL $OMEGA 0.2 ;24) METAB $OMEGA 0.4 ;25) ORAL UPTAKE ;VOLUME VARIANCES $ERROR IF(CMT.EQ.11) IPRED=A(11)/V11 W=THETA(17) IRES=IPRED-DV IWRES=IRES/W Y=IPRED*(1+W*ERR(1)) ;FIX BOTH MAYBE IF(CMT.EQ.23) IPRED=A(23)/V23 W=THETA(18) IRES=IPRED-DV IWRES=IRES/W Y=IPRED*(1+W*ERR(2)) +ERR(3) ;IF (ICALL.EQ.4) THEN ;DOWHILE (Y.LT.0) ;CALL SIMEPS(EPS) ;Y=A(4)/1260*(1+EPS(1)) +EPS(2) ;END DO ;END IF $EST METH=1 MAXEVAL=9999 PRINT=5 INTERACTION NOABORT SIGL=6 NSIG=3 CTYPE=4 NOTHETABOUNDTEST NOOMEGABOUNDTEST NOSIGMABOUNDTEST MSFO=test1.msf $SIGMA 0.5 FIX 0.4 1.5 $TABLE ID TIME CMT Y DV RHYD RHYL RMETD RMETL CDLV CLLV CVD CVL IPRED PRED CPREDI CRESI CWRESI CRES CWRES NOPRINT ONEHEADER FILE=test1.fit NOTITLE $TABLE ID TIME CMT ETAS(1:LAST) K13 K23 K30 K34 D1 ALAG2 F1 F2 NOPRINT ONEHEADER FILE=PARAM.tbl NOTITLE