;; Auther: Chunli Chen; ;; Uppsala Universitet; ;; 2015-10-13 ;; Multi-State Tuberculosis Pharmacometric Model ;; Update initial of transfer rates from Oskar's 20151013 final model (run406.mod); take final estimates from run406.lst file; No DEAD compartment; ;; Based on: =run11.mod $PROBLEM PKPD of RIF; H37Rv Mtb; C57BL/6 mouse; simulated data; ;; FD SigEmax (UB EMAX (600) EC50(300)); ;; FG Emax; ;; SDSL; ;; Estimate: SLOPE; KGR; AF; ;; FIX transfer rate constant from invitro work run406.lst $INPUT ID TIME DRUG DV DOSE AMT WT REALAMT FLAG TYPE SINGLE PO MOUSE M3DUM BQL ;; DV = ln(REALDV); ;; DOSE = AMT (ug/kg); ;; DRUG = 0, Natural Growth; DRUG = 1, CFU after Rifampicin admin; ;; REALAMT = WT*AMT, -99; WT = average WT in theory; ;; TYPE = 0, FLAG = 0, M3DUM = 0, Dose event; ;; TYPE = 1, FLAG = 1, Rifampciin PK data; ;; TYPE = 2, FLAG = 2, M3DUM = 2, CFU above LOQ; ;; TYPE = 3, FLAG = 2, CFU below LOQ (BQL=2.303); ;; M3DUM = 3, only one CFU after Rifampicin doses (1mg/kg, 2.83mg/kg, 8.88mg/kg, 26.4mg/kg, 97.5 mg/kg); ;; M3DUM = 4, multi CFU after Rifampicin dose (30mg/kg); ;; value of LOQ = 10, BQL = ln(LOQ) = ln(10) = 2.303 ;; PO = 1, Oral admin; PO = 0, Natural growth; ;; SINGLE = 0, Natural growth & multi Rifampicin dose admin; $DATA simulated_data_rif_pkpd_acute_mouse.csv IGNORE=@ $SUBROUTINE ADVAN13 TOL=9 $MODEL COMP=(RIF,DEFDOSE) COMP=(CENTRAL) COMP=(F) ;; Fast-Multiply M.tb compartment COMP=(S) ;; Slow-Multiply M.tb compartment COMP=(N) ;; Non-Multiply M.tb compartment $PK ;; -- Rifampicin Population PK -- ;; TVCL = THETA(1) IF(TIME.GE.48) TVCL = THETA(2) TVV = THETA(3) IF(DOSE.LE.1020) TVV = THETA(4) CL = TVCL V = TVV KE = CL/V TVKA = KE + THETA(5) TVF1 = THETA(6) IF(DOSE.EQ.0) TVF1 = 0 S2 = V KA = TVKA F1 = TVF1 F2 = 1 ;; -- Bacterial system parameters -- ;; TVAF = THETA(7)*EXP(ETA(1)) ;; Groups treated with RIF; Initial bacterial number in Fast Multiply State (CFU/ml) IF(DRUG.EQ.0) TVAF = THETA(8) ;; Groups for natural growth; Initial bacterial number in Fast Multiply State (CFU/ml) TVKGR = THETA(9) ;; Growth Rate of F (/hrs) TVKFSLIN = THETA(10)/100000 ;; Slope for time-dependent; F -> S (/hrs2); TVKFN = THETA(11)/1000000 ;; F -> N Rate (/hrs) FIX to in vitro; TVKSF = THETA(12)/10 ;; S -> F Rate (/hrs) FIX to in vitro; TVKSN = THETA(13) ;; S -> N Rate (/hrs) FIX to in vitro; TVKNS = THETA(14)/100 ;; N -> S Rate (/hrs) FIX to in vitro; ;; -- Drug effect parameters -- ;; TVFGIMAX = THETA(15) ;; Imax, Maximum inhibition effect TVFGIC50 = THETA(16) ;; IC50, inhibite Death Rate of F TVFDGAM = THETA(17) ;; Sigmoidicity factor, stimulate Death Rate of F TVFDEMAX = THETA(18) ;; Emax, Maximum stimulation effect TVFDEC50 = THETA(19) ;; EC50, increase Death Rate of F TVSDSL = THETA(20) ;; Linear function, stimulate Death Rate of S AF = TVAF KGR = TVKGR KFSLIN = TVKFSLIN KSF = TVKSF KFN = TVKFN KSN = TVKSN KNS = TVKNS FGIMAX = TVFGIMAX FGIC50 = TVFGIC50 FDGAM = TVFDGAM FDEMAX = TVFDEMAX FDEC50 = TVFDEC50 SDSL = TVSDSL ;; -- Initilization of each compartment -- ;; A_0(1) = AMT A_0(2) = 0.00001 A_0(3) = AF A_0(4) = 0.00001 A_0(5) = 0.00001 $DES RIFCB = A(2)/V ;; RIF blood concentration IF(DRUG.EQ.0) RIFCB = 0 FD = (FDEMAX*RIFCB**FDGAM)/(FDEC50**FDGAM+RIFCB**FDGAM) ;;Rif effect stimulating Death Rate of F SD = SDSL*RIFCB ;;Rif effect stimulating Death Rate of S FG = 1-((FGIMAX*RIFCB)/(FGIC50+RIFCB)) ;;Rif effect inhibiting Geath Rate of F KFS = KFSLIN*T ;;Time-dependent linear(slope) transit F -> S DADT(1) = -KA*A(1) ;; Default Dose Comp. DADT(2) = KA*A(1)-KE*A(2) ;; Rif. Conc DADT(3) = KGR*A(3)*FG-KFS*A(3)+KSF*A(4)-KFN*A(3)-FD*A(3) ;; Fast Multi. DADT(4) = KFS*A(3)-KSF*A(4)-KSN*A(4)+KNS*A(5)-SD*A(4) ;; Slow Multi. DADT(5) = KFN*A(3)+KSN*A(4)-KNS*A(5) ;; Non-Multi. $ERROR COM2 = 0 IF(FLAG.EQ.1) COM2 = 1 COM3 = 0 IF(FLAG.EQ.2) COM3 = 1 DEL = 1E-6 ;; -- CALCULATE TIME AFTER DOSE -- ;; IF(AMT.GT.0)RTAD=TIME TAD=TIME-RTAD ;; -- RIF PK ERROR MODEL -- ;; DOSECMT = A(1) CENTRALCMT = A(2) IF(FLAG.EQ.1) THEN IPRED = A(2)/V IRES = DV - IPRED PROP = IPRED*SQRT(SIGMA(1,1)) IWRES = IRES/(PROP+0.000001) Y1 = IPRED+IPRED*EPS(1) ENDIF ;; -- Multi-State Disease Model ERROR MODEL -- ;; FBAC = A(3) SBAC = A(4) NBAC = A(5) TBAC = A(3)+A(4)+A(5) IPRED = LOG(A(3)+A(4)) ; LOG=LN SIG = SQRT(SIGMA(2,2)) IRES = DV - IPRED IWRES = IRES/(SIG+DEL) ; - M3 METHODS TO HANDLE RIF PD LOQ DATA - ; LLOQ = LOG(10) DUM = (LLOQ-IPRED)/SIG CUMD = PHI(DUM) IF(FLAG.EQ.2.AND.TYPE.EQ.2) THEN F_FLAG = 0 Y2 = IPRED + EPS(2) ELSE F_FLAG = 1 Y2 = CUMD END IF Y = COM2*Y1 + COM3*Y2 $THETA 79.321 FIX ; 1.CL (at day 1 and day 2) $THETA 131.911 FIX ; 2.CL (at Time >= day 3) $THETA 1249.140 FIX ; 3.V (at Dose > lowest dose level $THETA 2278.740 FIX ; 4.V (at Dose == lowest dose level(1.02 mg/kg) $THETA 0.994 FIX ; 5.TVKA $THETA 0.656 FIX ; 6.F1 $THETA (0,332089.0) ; 7.AF of RIF system specific $THETA (0,8348.540) ; 8.AF of natural growth system $THETA (0,0.033255) ; 9.KGR $THETA (0,2.956210) ; 10.KFS LIN $THETA 0.037375 FIX ; 11.KFN/1000000 (in vitro: 0.897 /24 = 0.037375)/1000000 $THETA 0.006042 FIX ; 12.KSF/10 (in vitro: 0.145 /24 = 0.006042)/10 $THETA 0.007750 FIX ; 13.KSN (in vitro: 0.186 /24 = 0.00775) $THETA 0.005125 FIX ; 14.KNS/100 (in vitro: 0.123 /24 = 0.005125)/100 $THETA (0,0.717058,1) ; 15.FGIMAX $THETA (0,0.039927) ; 16.FGIC50 $THETA (0,2.192450) ; 17.FDGAM $THETA (0,67.08230,600) ; 18.FDEMAX $THETA (0,98.50150,300) ; 19.FDEC50 $THETA (0,0.004911) ; 20.SDSL $OMEGA 0 FIX $SIGMA 0.0235 FIX $SIGMA 0.216544 $ESTIMATION METHOD=1 LAPLACIAN INTER PRINT=3 MAXEVAL=0 NSIG=3 SIGL=9 NOABORT ;$COVARIANCE $TABLE ID TIME DV PRED IPRED WRES IWRES CWRES TYPE DRUG DOSE FLAG EVID M3DUM RIFCB DOSECMT CENTRALCMT FBAC SBAC NBAC TBAC NOPRINT ONEHEADER FILE=sdtabrif_pkpd_acute_mouse_output_original