;; 1. Based on: 282 ;; 2. Description: Col & Mero Wild + Resistant ;; x1. Author: Anders Kristoffersson $PROBLEM Col & Mero Wild + Resistant ;; Combined model ;; ;; 3. Label: ;; ;; 4. Structural model: ;; Binding Model, new data ;; 5. Covariate model: ;; No covariates ;; 6. Inter-individual variability: ;; 7. Inter-occasion variability: ;; 8. Residual variability: ;; Proportional ;; 9. Estimation: ;; LAPLACIAN $INPUT ID ID2 Ccol Cmer TYPE EVID CMT TIME NOP=DROP NOB=DROP G10=DROP NDV=DROP DV AMT L2 REPL BACT BLOQ DILcol DILmer STR $DATA ColistinMeropenem_Interaction_simulated.csv IGNORE=@ ; $SUBROUTINE ADVAN13 TOL9 $MODEL COMP=(S) ;1. Compartment S,suspectible COMP=(R) ;2. Compartment R,resting COMP=(CA2) ;3. Cmer Meropenem COMP=(CE2) ;4. CE2 Meropenem (not used) COMP=(BINDOFF) ;5. Bind Off Mero (not used) COMP=(CA1) ;6. C Colistin conc COMP=(CE1) ;7. CE1 Colistin COMP=(BINDOFF1) ;8.Bind Off Col COMP=(SM) ;9. Compartment S,suspectible,mutant COMP=(RM) ;10. Compartment R,resting,mutant $PK MERO=0 IF(TYPE.EQ.1.OR.TYPE.EQ.3) MERO=1 ; TYPE=1 Meropenem, TYPE=2 Colistin, TYPE=3 Combination, TYPE=4 Control, TYPE=5 Control COL=0 IF(TYPE.EQ.2.OR.TYPE.EQ.3) COL=1 CONTR=0 IF(TYPE.EQ.4.OR.TYPE.EQ.5) CONTR=1 TVKGA=0 IF(BACT.EQ.2)TVKGA = THETA(1) ;ATCC Rate of growth TVKGP=0 IF(BACT.EQ.1)TVKGP = THETA(2) ;PLO6 Rate of growth TVKK = THETA(3) ; Natural death rate TVEMAX1 =0 IF(COL.EQ.1.AND.BACT.EQ.2) TVEMAX1 = THETA(4) ;ATCC + COL TVSLOP1 =0 IF(COL.EQ.1.AND.BACT.EQ.1) TVSLOP1 = THETA(5) ;ARU + COL TVEMAX2=0 IF(MERO.EQ.1.AND.BACT.EQ.2) TVEMAX2 = THETA(6) ;ATCC + MERO TVEMAX3=0 IF(MERO.EQ.1.AND.BACT.EQ.1) TVEMAX3 = THETA(7) ;ARU + MERO TVEC51=0 IF(COL.EQ.1.AND.BACT.EQ.2) TVEC51 = THETA(8) ;ATCC + COL TVSLOPAM=0 IF(MERO.EQ.1.AND.BACT.EQ.2) TVSLOPAM = THETA(9) ;ATCC + MERO TVEC53=0 IF(MERO.EQ.1.AND.BACT.EQ.1) TVEC53 = THETA(10) ;ARU + MERO IF(COL.EQ.1) TVGAMC = THETA(11) ;COL IF(MERO.EQ.1.AND.BACT.EQ.2) TVGAMA = THETA(12) ;ATCC + MERO IF(MERO.EQ.1.AND.BACT.EQ.1) TVGAMP = THETA(26) ;ARU + MERO TVBMAX = 10**THETA(13) ;Bmax log10 TVKON51=0 IF(COL.EQ.1.AND.BACT.EQ.2) TVKON51 = THETA(14) ;COL + ATCC TVKON52=0 IF(COL.EQ.1.AND.BACT.EQ.1) TVKON52 = THETA(15) ;COL + PLO6 TVKOFFC=0 IF(COL.EQ.1) TVKOFFC = THETA(16) ;COL IF(MERO.EQ.1) TVKOFFM = THETA(17) ;MERO TVKONCA=0 IF(COL.EQ.1.AND.BACT.EQ.2) TVKONCA = THETA(18) ;COL + ATCC TVKONCP=0 IF(COL.EQ.1.AND.BACT.EQ.1) TVKONCP = THETA(19) ;COL + PLO6 TVKONMA=0 IF(MERO.EQ.1.AND.BACT.EQ.2) TVKONMA = THETA(20) ;ATCC + MERO TVKONMP=0 IF(MERO.EQ.1.AND.BACT.EQ.1) TVKONMP = THETA(21) ;ARU + MERO IF(COL.EQ.1) TVGAM3C = THETA(22) ; COL IF(COL.EQ.1) TVGAM1 = THETA(23) ;COL ;Dynamic growth rate frac increase KGDxS = 1 IF (ID2>18) KGDxS = (1+THETA(35)); %ID>18 --> dynamic system ;--Mutant parameters ;Mutant suceptibillity shift, handle as common concetration shift for ATCC and ARU MSLOPAM = TVSLOPAM/((1+THETA(31))**TVGAMA) ; EC53M = TVEC53*(1+THETA(31)) ;Decrease mutant KG KGAFM = THETA(33) KGPFM = THETA(34) KGAM = KGDxS*TVKGA*(1-KGAFM) ;frac decrease KGPM = KGDxS*TVKGP*(1-KGPFM) ;Mutant fraction MUTA = 10**(-THETA(29)) ;ATCC MUTP = MUTA; ARU, same as ATCC MUT=0 IF(MERO.EQ.1.AND.BACT.EQ.2) MUT = MUTA ;ATCC + MERO IF(MERO.EQ.1.AND.BACT.EQ.1) MUT = MUTP ;ARU + MERO NMUT = 0 IF (AMT*MUT>=0) NMUT = AMT*MUT ;Number mutant ;Initialize A_0(2)=0 ; R A_0(3)=Cmer ; Meropenem A_0(4)=0 ; Meropenem adaptive res on (not used) A_0(5)=1 ; Meropenem adaptive res off (not used) A_0(6)=Ccol ; Colistin A_0(7)=0 ; Colistin adaptive res on (not used) A_0(8)=1 ; Colistin adaptive res off (not used) A_0(9)=NMUT ; Smut A_0(10)=0 ; Rmut KGA = KGDxS*TVKGA*EXP(ETA(1)) KGP = KGDxS*TVKGP*EXP(ETA(1)) KK = TVKK EMAX1 = TVEMAX1 SLOP1 = TVSLOP1 EMAX2 = TVEMAX2 EMAX3 = TVEMAX3 EC51 = TVEC51 SLOPAM = TVSLOPAM EC53 = TVEC53 GAMA = TVGAMA GAMP = TVGAMP GAMC = TVGAMC BMAX = TVBMAX KON51 = TVKON51 KON52 = TVKON52 KOFFC = TVKOFFC KOFFM = TVKOFFM KONCA = TVKONCA KONCP = TVKONCP KONMA = TVKONMA KONMP = TVKONMP GAM3C = TVGAM3C GAM1 = TVGAM1 ;---- Observed C ----- KE1 = (0.02) ; Meropenem degeneration value obtained from exp KE2 = 0 ; Colistin degeneration value IF(A_0(6).EQ.0.04162.AND.TIME.LT.8) KE2 = 0.059 ;ATCC + COL IF(A_0(6).EQ.0.04162.AND.TIME.GE.8) KE2 = 0.003 IF(A_0(6).EQ.0.1877.AND.TIME.LT.8) KE2 = 0.079 IF(A_0(6).EQ.0.1877.AND.TIME.GE.8) KE2 = 0.021 IF(A_0(6).EQ.0.2960.AND.TIME.LT.8) KE2 = 0.042 IF(A_0(6).EQ.0.2960.AND.TIME.GE.8) KE2 = 0.042 IF(A_0(6).EQ.0.7753.AND.TIME.LT.8) KE2 = 0.003 IF(A_0(6).EQ.0.7753.AND.TIME.GE.8) KE2 = 0.017 IF(A_0(6).EQ.2.182.AND.TIME.LT.8) KE2 = 0.038 IF(A_0(6).EQ.2.182.AND.TIME.GE.8) KE2 = 0.015 IF(A_0(6).EQ.4.305.AND.TIME.LT.8) KE2 = 0.0076 IF(A_0(6).EQ.4.305.AND.TIME.GE.8) KE2 = 0.00061 IF(A_0(6).EQ.12.024.AND.TIME.LT.8) KE2 = 0.012 IF(A_0(6).EQ.12.024.AND.TIME.GE.8) KE2 = 0.0033 IF(A_0(6).EQ.0.08091.AND.TIME.LT.8) KE2 = 0.16 ;ARU + COL IF(A_0(6).EQ.0.08091.AND.TIME.GE.8) KE2 = 0.039 IF(A_0(6).EQ.0.2483.AND.TIME.LT.8) KE2 = 0.031 IF(A_0(6).EQ.0.2483.AND.TIME.GE.8) KE2 = 0.070 IF(A_0(6).EQ.0.9582.AND.TIME.LT.8) KE2 = 0.049 IF(A_0(6).EQ.0.9582.AND.TIME.GE.8) KE2 = 0.093 IF(A_0(6).EQ.2.672.AND.TIME.LT.8) KE2 = 0.037 IF(A_0(6).EQ.2.672.AND.TIME.GE.8) KE2 = 0.056 IF(A_0(6).EQ.5.113.AND.TIME.LT.8) KE2 = 0.027 IF(A_0(6).EQ.5.113.AND.TIME.GE.8) KE2 = 0.022 IF(A_0(6).EQ.11.471.AND.TIME.LT.8) KE2 = 0.011 IF(A_0(6).EQ.11.471.AND.TIME.GE.8) KE2 = 0.0058 IF(A_0(6).EQ.24.099.AND.TIME.LT.8) KE2 = 0.0078 IF(A_0(6).EQ.24.099.AND.TIME.GE.8) KE2 = 0.0021 CA025=0 IF(A_0(6).EQ.0.205.OR.A_0(6).EQ.0.199.OR.A_0(6).EQ.0.195) CA025=1 CA026=0 IF(A_0(6).EQ.0.211.OR.A_0(6).EQ.0.223.OR.A_0(6).EQ.0.187) CA026=1 IF(CA025.EQ.1.AND.TIME.LT.8) KE2 = 0.196 ; Intended conc 0.25 combined exp IF(CA025.EQ.1.AND.TIME.GE.8) KE2 = 0.0534 IF(CA026.EQ.1.AND.TIME.LT.8) KE2 = 0.196 IF(CA026.EQ.1.AND.TIME.GE.8) KE2 = 0.0534 IF(A_0(6).EQ.0.431.AND.TIME.LT.8) KE2 = 0.111 ; Intended conc 0.5 combined exp IF(A_0(6).EQ.0.431.AND.TIME.GE.8) KE2 = 0.126 IF(A_0(6).EQ.0.411.AND.TIME.LT.8) KE2 = 0.111 IF(A_0(6).EQ.0.411.AND.TIME.GE.8) KE2 = 0.126 IF(A_0(6).EQ.0.408.AND.TIME.LT.8) KE2 = 0.111 IF(A_0(6).EQ.0.408.AND.TIME.GE.8) KE2 = 0.126 IF(A_0(6).EQ.0.482.AND.TIME.LT.8) KE2 = 0.111 IF(A_0(6).EQ.0.482.AND.TIME.GE.8) KE2 = 0.126 IF(A_0(6).EQ.0.479.AND.TIME.LT.8) KE2 = 0.111 IF(A_0(6).EQ.0.479.AND.TIME.GE.8) KE2 = 0.126 IF(A_0(6).EQ.0.465.AND.TIME.LT.8) KE2 = 0.111 IF(A_0(6).EQ.0.465.AND.TIME.GE.8) KE2 = 0.126 IF(A_0(6).EQ.0.673.AND.TIME.LT.8) KE2 = 0.0503 ; Intended conc 1 combined exp IF(A_0(6).EQ.0.673.AND.TIME.GE.8) KE2 = 0.0143 IF(A_0(6).EQ.0.71.AND.TIME.LT.8) KE2 = 0.0503 IF(A_0(6).EQ.0.71.AND.TIME.GE.8) KE2 = 0.0143 IF(A_0(6).EQ.1.467.AND.TIME.LT.8) KE2 = 0.0330 ; Intended conc 2 combined exp IF(A_0(6).EQ.1.467.AND.TIME.GE.8) KE2 = 0.0367 IF(A_0(6).EQ.1.234.AND.TIME.LT.8) KE2 = 0.0330 IF(A_0(6).EQ.1.234.AND.TIME.GE.8) KE2 = 0.0367 IF(A_0(6).EQ.1.433.AND.TIME.LT.8) KE2 = 0.0330 IF(A_0(6).EQ.1.433.AND.TIME.GE.8) KE2 = 0.0367 IF(A_0(6).EQ.1.657.AND.TIME.LT.8) KE2 = 0.0330 IF(A_0(6).EQ.1.657.AND.TIME.GE.8) KE2 = 0.0367 IF(A_0(6).EQ.1.418.AND.TIME.LT.8) KE2 = 0.0330 IF(A_0(6).EQ.1.418.AND.TIME.GE.8) KE2 = 0.0367 IF(A_0(6).EQ.3.523.AND.TIME.LT.8) KE2 = 0.0351 ; Intended conc 4 combined exp IF(A_0(6).EQ.3.523.AND.TIME.GE.8) KE2 = 0.0245 IF(A_0(6).EQ.3.447.AND.TIME.LT.8) KE2 = 0.0351 IF(A_0(6).EQ.3.447.AND.TIME.GE.8) KE2 = 0.0245 IF(A_0(6).EQ.3.288.AND.TIME.LT.8) KE2 = 0.0351 IF(A_0(6).EQ.3.288.AND.TIME.GE.8) KE2 = 0.0245 IF(A_0(6).EQ.3.031.AND.TIME.LT.8) KE2 = 0.0351 IF(A_0(6).EQ.3.031.AND.TIME.GE.8) KE2 = 0.0245 IF(A_0(6).EQ.7.669.AND.TIME.LT.8) KE2 = 0.00226 ; Intended conc 8 combined exp IF(A_0(6).EQ.7.669.AND.TIME.GE.8) KE2 = 0.0001 IF(A_0(6).EQ.6.622.AND.TIME.LT.8) KE2 = 0.00226 IF(A_0(6).EQ.6.622.AND.TIME.GE.8) KE2 = 0.0001 $DES CA2=A(3) ; MERO CE2=0;A(4) CA1=A(6) ; COL CE1=A(7) AT = A(1)+A(2)+A(9)+A(10) ;DRUG EFFECT COLA = 0 IF(COL.EQ.1.AND.BACT.EQ.2) COLA = EMAX1*(CA1)**GAMC/(EC51**GAMC+(CA1)**GAMC) ;ATCC + COL COLP = 0 IF(COL.EQ.1.AND.BACT.EQ.1) COLP = SLOP1*CA1**GAMC ;ARU + COL MEROA = 0 IF(MERO.EQ.1.AND.BACT.EQ.2) MEROA = SLOPAM*CA2**GAMA ;ATCC + MERO MEROP = 0 IF(MERO.EQ.1.AND.BACT.EQ.1) MEROP = EMAX3*(CA2)**GAMP/(EC53**GAMP+(CA2)**GAMP) ;ARU + MER ;Mutant MEROAM = 0 IF(MERO.EQ.1.AND.BACT.EQ.2) MEROAM = MSLOPAM*CA2**GAMA; ;ATCC + MERO MEROPM = 0 IF(MERO.EQ.1.AND.BACT.EQ.1) MEROPM = EMAX3*(CA2)**GAMP/(EC53M**GAMP+(CA2)**GAMP) ;ARU + MER ;INHIBITION OF DRUG EFFECT COLA1 = 0 IF(COL.EQ.1.AND.BACT.EQ.2) COLA1 = COLA*(1-CE1**GAM1) ;ATCC + COL COLP1 = 0 IF(COL.EQ.1.AND.BACT.EQ.1) COLP1 = COLP*(1-CE1**GAM1) ;ARU + COL MEROA1 = 0 IF(MERO.EQ.1.AND.BACT.EQ.2) MEROA1 = MEROA*(1-CE2) ;ATCC + MERO MEROP1 = 0 IF(MERO.EQ.1.AND.BACT.EQ.1) MEROP1 = MEROP*(1-CE2) ; ARU + MERO ;Mutant MEROA1M = 0 IF(MERO.EQ.1.AND.BACT.EQ.2) MEROA1M = MEROAM*(1-CE2) ;ATCC + MERO MEROP1M = 0 IF(MERO.EQ.1.AND.BACT.EQ.1) MEROP1M = MEROPM*(1-CE2) ; ARU + MERO ;COMBINATION DRUGA = 0 IF(TYPE.EQ.3.AND.BACT.EQ.2)THEN DRUGA = (COLA1*(1+MEROA1/(COLA1+MEROA1))**(THETA(27)) + MEROA1*(1+COLA1/(COLA1+MEROA1))**(THETA(27))) ; ATCC + COMB DRUG = DRUGA ADD = MEROA1 + COLA1 ENDIF DRUGB = 0 IF(TYPE.EQ.3.AND.BACT.EQ.1) THEN DRUGB = (COLP1*(1+MEROP1/(COLP1+MEROP1))**(THETA(28)) + MEROP1*(1+COLP1/(COLP1+MEROP1))**(THETA(28))) ; PLO6 + COMB DRUG = DRUGB ADD = COLP1 + MEROP1 ENDIF ;Mutant DRUGAM = 0 IF(TYPE.EQ.3.AND.BACT.EQ.2) THEN DRUGAM = (COLA1*(1+MEROA1M/(COLA1+MEROA1M))**(THETA(27)) + MEROA1M*(1+COLA1/(COLA1+MEROA1M))**(THETA(27))) ; ATCC + COMB DRUGM = DRUGAM ADDM = COLA1 + MEROA1M ENDIF DRUGBM = 0 IF(TYPE.EQ.3.AND.BACT.EQ.1) THEN DRUGBM = (COLP1*(1+MEROP1M/(COLP1+MEROP1M))**(THETA(28)) + MEROP1M*(1+COLP1/(COLP1+MEROP1M))**(THETA(28))) ; PLO6 + COMB DRUGM = DRUGBM ADDM = COLP1 + MEROP1M ENDIF ;CONVERSION FROM ACTIVE TO RESTING COMP FEEDA=0 IF(BACT.EQ.2) FEEDA=(KGA-KK)/BMAX ;ATCC ;Maximum conversion rate btw active/resting cell FEEDP=0 IF(BACT.EQ.1) FEEDP=(KGP-KK)/BMAX ; PLO6 SRA=0 IF(BACT.EQ.2) SRA=FEEDA*AT ;ATCC Conversion rate btw active/resting cell dependent on cell number SRP=0 IF(BACT.EQ.1) SRP=FEEDP*AT ;PLO6 ; RATE FOR DEV OF KON KON1CA=0 IF(COL.EQ.1.AND.BACT.EQ.2) KON1CA = (KONCA*CA1**GAM3C)/(CA1**GAM3C + KON51**GAM3C) ; ATCC + COL KON1CP=0 IF(COL.EQ.1.AND.BACT.EQ.1) KON1CP = (KONCP*CA1**GAM3C)/(CA1**GAM3C + KON52**GAM3C) ; PLO6 + COL DADT(1)=0 ;S IF(COL.EQ.1.AND.BACT.EQ.2) DADT(1)=KGA*A(1)-(KK+COLA1)*A(1) - SRA*A(1) ;ATCC + COL IF(COL.EQ.1.AND.BACT.EQ.1) DADT(1)=KGP*A(1)-(KK+COLP1)*A(1) - SRP*A(1) ;ARU + COL IF(MERO.EQ.1.AND.BACT.EQ.2) DADT(1)=KGA*A(1)-(KK+MEROA1)*A(1) - SRA*A(1) ;ATCC + MERO IF(MERO.EQ.1.AND.BACT.EQ.1) DADT(1)=KGP*A(1)-(KK+MEROP1)*A(1) - SRP*A(1) ;ARU + MERO IF(TYPE.EQ.3.AND.BACT.EQ.2) DADT(1)=KGA*A(1)-(KK+DRUGA)*A(1) - SRA*A(1) ;ATCC + COMB IF(TYPE.EQ.3.AND.BACT.EQ.1) DADT(1)=KGP*A(1)-(KK+DRUGB)*A(1) - SRP*A(1) ;PLO6 + COMB IF(CONTR.EQ.1.AND.BACT.EQ.2) DADT(1)=KGA*A(1)-(KK)*A(1) - SRA*A(1) ; ATCC +CONTROL IF(CONTR.EQ.1.AND.BACT.EQ.1) DADT(1)=KGP*A(1)-(KK)*A(1) - SRP*A(1) ;PLO6 + CONTROL DADT(2)=0 ; R IF(BACT.EQ.2) DADT(2)=-KK*A(2) + SRA*A(1) ;ATCC IF(BACT.EQ.1) DADT(2)=-KK*A(2) + SRP*A(1) ;PLO6 DADT(3)=0 IF(MERO.EQ.1) DADT(3)=-(KE1+DILmer)*A(3) ; Mero ;Mer adaptive res on (not used) DADT(4)=0 ;IF(MERO.EQ.1.AND.BACT.EQ.2)DADT(4)=KONMA*A(5)-KOFFM*A(4) ;ATCC + MERO ;IF(MERO.EQ.1.AND.BACT.EQ.1)DADT(4)=KONMP*A(5)-KOFFM*A(4) ;ARU + MERO ;Mer adaptive res on (not used) DADT(5)=0 ;IF(MERO.EQ.1.AND.BACT.EQ.2) DADT(5)=KOFFM*A(4)-KONMA*A(5) ;ATCC + MERO ;IF(MERO.EQ.1.AND.BACT.EQ.1) DADT(5)=KOFFM*A(4)-KONMP*A(5) ;ARU + MERO DADT(6)=0 IF(COL.EQ.1) DADT(6)=-(KE2+DILcol)*A(6) ; Colistin ;Colistin adaptive res on DADT(7)=0 IF(COL.EQ.1.AND.BACT.EQ.2) DADT(7)=KON1CA*A(8)-KOFFC*A(7) ; ATCC + Colistin IF(COL.EQ.1.AND.BACT.EQ.1) DADT(7)=KON1CP*A(8)-KOFFC*A(7) ;ARU + Colistin ;Colistin adaptive res off DADT(8)=0 IF(COL.EQ.1.AND.BACT.EQ.2) DADT(8)=KOFFC*A(7)-KON1CA*A(8) ; ATCC + Colistin IF(COL.EQ.1.AND.BACT.EQ.1) DADT(8)=KOFFC*A(7)-KON1CP*A(8) ;ARU + Colistin ;S mut DADT(9)=0 IF(COL.EQ.1.AND.BACT.EQ.2) DADT(9)=KGAM*A(9)-(KK+COLA1)*A(9) - SRA*A(9) ;ATCC + COL IF(COL.EQ.1.AND.BACT.EQ.1) DADT(9)=KGPM*A(9)-(KK+COLP1)*A(9) - SRP*A(9) ;ARU + COL IF(MERO.EQ.1.AND.BACT.EQ.2) DADT(9)=KGAM*A(9)-(KK+MEROA1M)*A(9) - SRA*A(9) ;ATCC + MERO IF(MERO.EQ.1.AND.BACT.EQ.1) DADT(9)=KGPM*A(9)-(KK+MEROP1M)*A(9) - SRP*A(9) ;ARU + MERO IF(TYPE.EQ.3.AND.BACT.EQ.2) DADT(9)=KGAM*A(9)-(KK+DRUGAM)*A(9) - SRA*A(9) ;ATCC + COMB IF(TYPE.EQ.3.AND.BACT.EQ.1) DADT(9)=KGPM*A(9)-(KK+DRUGBM)*A(9) - SRP*A(9) ;PLO6 + COMB IF(CONTR.EQ.1.AND.BACT.EQ.2) DADT(9)=KGAM*A(9)-(KK)*A(9) - SRA*A(9) ; ATCC +CONTROL IF(CONTR.EQ.1.AND.BACT.EQ.1) DADT(9)=KGPM*A(9)-(KK)*A(9) - SRP*A(9) ;PLO6 + CONTROL ;R mut DADT(10)=0 IF(BACT.EQ.2) DADT(10)=-KK*A(10) + SRA*A(9) ;ATCC IF(BACT.EQ.1) DADT(10)=-KK*A(10) + SRP*A(9) ;PLO6 $ERROR LLOQ=LOG(10) ;LOQ=10 A1=A(1) A2=A(2) A3=A(3) A4=A(4) A5=A(5) A6=A(6) A7=A(7) A8=A(8) A9=A(9) A10=A(10) ATOT=A1+A2 +A9 + A10 ; S+ R + Smut + Rmut IF(ATOT<1e-5) ATOT = 1e-5 IPRED=LOG(ATOT) ;LOG=LN in NONMEM IRES = DV-IPRED W=SQRT(SIGMA(1)+SIGMA(2))*LOG(10) ;Set on log10 IWRES = IRES/W ;Replicate number for L2 method AAA=0 AAB=0 AAC=0 AAD=0 IF(REPL.EQ.1) AAA=1 IF(REPL.EQ.2) AAB=1 IF(REPL.EQ.3) AAC=1 IF(REPL.EQ.4) AAD=1 IF(BLOQ.EQ.0) THEN ;DV>LOQ F_FLAG=0 Y=IPRED+LOG(10)*(EPS(1)+AAA*EPS(2)+AAB*EPS(3)+AAC*EPS(4)+AAD*EPS(5)) ;Set on log10 ENDIF IF(BLOQ.EQ.1) THEN ;DV 0 synergistic <0 antagonist) (-10,1.3,10) ; 28. Interaction ARU(=0 No interaction,not 0 Interaction > 0 synergistic <0 antagonist) (0,2.83) ; 29. -LOG10 MUTF ATCC 0 FIX ; 30. -LOG10 MUTF ARU (0,22.5) ; 31. Concentration shift EC50 / Slope(MEROMfrac increase) 0 FIX ; 32. - 0 FIX ; 33. decrease KG MEROM ATCC (0,0.536,1) ; 34. decrease KG MEROM ARU(set as frac decrease) (0,0.332,10) ; 35. KG stat x dyn(set as frac increase) $OMEGA 0 FIX ; ETA KG1 $SIGMA 0.422 ; S1 set on log10 $SIGMA BLOCK(1) 0.0364 ; S2 seton log10 $SIGMA BLOCK(1) SAME $SIGMA BLOCK(1) SAME $SIGMA BLOCK(1) SAME $ESTIMATION METHOD=1 LAPLACIAN NUMERICAL SIGDIG=3 SIGL=9 SIGLO=9 MAXEVAL=0 POSTHOC PRINT=1 NOABORT MSFO=msfb282-final_tidyup $COVARIANCE UNCONDITIONAL $TABLE ID TYPE BACT TIME EVID Ccol Cmer IPRED IWRES CWRES NOPRINT ONEHEADER FILE=sdtab282-finall_tidyup $TABLE ID TYPE BACT TIME EVID Ccol Cmer KE2 AT A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 KGA KGAM KGP KGPM MEROA MEROA1 MEROP MEROP1 MEROAM MEROA1M MEROPM MEROP1M COLA COLA1 COLP COLP1 DRUGA DRUGB DRUGAM DRUGBM DRUG ADD DRUGM ADDM IPRED NOPRINT ONEHEADER FILE=patab282-finall_tidyup