$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=TEST8E1.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=test2.fit NOTITLE $TABLE ID TIME CMT ETAS(1:LAST) K13 K23 K30 K34 D1 ALAG2 F1 F2 NOPRINT ONEHEADER FILE=PARAM.tbl NOTITLE