;; 1. Based on: 119 ;; 2. Description: No Health effect ;; x1. Author: user $PROBLEM 1 $INPUT ID ; Patient ID TIME ; Time of sample DV ; Dependent variable (natural logarithm of observed concentration, ng/mL) WT ; Body weight (covariate) EVID ; Event ID record MDV ; Missing dependent variable (1 = missing) AMT ; Dose amount (mg) CMT ; Compartment AGE ; Age (covariate, years) MAT ; Matrix (covariate; 1 = capillary, 2 = venous) OCC ; Dose occasion (1 = first dose, 2 = second dose , 3 = third dose) $DATA Simulated_run1.csv IGNORE = # $SUBROUTINE ADVAN5 TRANS1 $MODEL COMP = (1) ; Dose COMP = (2) ; Central compartment COMP = (3) ; First peripheral compartment COMP = (4) ; Second peripheral compartment COMP = (5) ; Transit compartment 1 COMP = (6) ; Transit compartment 2 $PK ;------------------------------------Dose occasion covariate---------------------------------------------------------------------- F1COVD = (1 + THETA(10) * (OCC - 1)) ; Linear covariate relationship for dose occasion ;---------------------------------------------------------------------------------------------------------------------------------------- ;------------------------------------Age covariate----------------------------------------------------------------------------------- EM50 = THETA(11) ; Age to reach 50% of full maturation HILL = THETA(12) ; Hill coefficient MF = ((AGE)**HILL) / (((EM50)**HILL) + ((AGE)**HILL) ) ; Age-maturation relationship ;---------------------------------------------------------------------------------------------------------------------------------------- ;------------------------------------ Scaling factor for venous to capillary concentration ---------------------------------- IF(MAT.EQ.2) SCALEVC = 1 ; Capillary concentration IF(MAT.EQ.1) SCALEVC = 1 + THETA(9) ; Scaling for venous concentration ;---------------------------------------------------------------------------------------------------------------------------------------- ;------------------------------------ Inter-dose occasion variability (IOV) ---------------------------------------------------- OC1 = 0 ; Initial value, first dose occasion OC2 = 0 ; Initial value, second dose occasion OC3 = 0 ; Initial value, third dose occasion IF(OCC.EQ.1) OC1 = 1 ; First dose occasion IF(OCC.EQ.2) OC2 = 1 ; Second dose occasion IF(OCC.EQ.3) OC3 = 1 ; Third dose occasion IOV1 = ETA(9) * OC1 + ETA(10) * OC2 + ETA(11) * OC3 ; IOV for relative bioavailability IOV2 = ETA(12) * OC1 + ETA(13) * OC2 + ETA(14) * OC3 ; IOV for mean transit time ;---------------------------------------------------------------------------------------------------------------------------------------- TVCL = THETA(1) * MF * ((WT / 54)**0.75) ; Population clearance CL = TVCL * EXP(ETA(1)) ; Individual TVV2 = THETA(2) * ((WT / 54)**1) ; Population central volume V2 = TVV2 * EXP(ETA(2)) ; Individual central volume TVQ1 = THETA(3) * ((WT / 54)**0.75) ; Population inter-compartment clearance 1 Q1 = TVQ1 * EXP(ETA(3)) ; Individual inter-compartment clearance 1 TVV3 = THETA(4) * ((WT / 54)**1) ; Population peripheral volume 1 V3 = TVV3 * EXP(ETA(4)) ; Individual peripheral volume 1 TVQ2 = THETA(5) * ((WT / 54)**0.75) ; Population inter-compartment clearance 2 Q2 = TVQ2* EXP(ETA(5)) ; Individual inter-compartment clearance 2 TVV4 = THETA(6) * ((WT / 54)**1) ; Population peripheral volume 2 V4 = TVV4 * EXP(ETA(6)) ; Individual peripheral volume 2 TVMT = THETA(7) ; Population mean transit time MT = TVMT * EXP(ETA(7) + IOV2) ; Individual mean transit time TVF1 = THETA(8) * F1COVD ; Population relative bioavailability F1 = TVF1 * EXP(ETA(8) + IOV1) ; Individual relative bioavailability NN = 2 ; Number of transit compartments KTR = (NN + 1) / MT ; Transit rate constant K15 = KTR ; Transit rate constant (COMP 1 --> 5) K56 = KTR ; Transit rate constant (COMP 5 --> 6) K62 = KTR ; Transit rate constant (COMP 6 --> 2) K20 = CL / V2 ; Elimination rate constant (COMP 2 --> 0) K23 = Q1 / V2 ; Distribution rate constant (COMP 2 --> 3) K32 = Q1 / V3 ; Distribution rate constant (COMP 3 --> 2) K24 = Q2 / V2 ; Distribution rate constant (COMP 2 --> 4) K42 = Q2 / V4 ; Distribution rate constant (COMP 4 --> 2) S2 = V2 /1000 ; Scaling for central volume $ERROR IPRED = A(2) / S2 ; Predicted plasma concentration IPRED = IPRED * SCALEVC ; Scaling factor (venous to capillary) IF(IPRED.GT.0) IPRED = LOG(IPRED) ; Natural logarithm of predictions W = SQRT(SIGMA(1,1)) ; Residual error IRES = IPRED - DV ; Individual residual error IWRES = IRES / W ; Individually weighted residual error Y = IPRED + EPS(1) ; Additive residual error $THETA ; Initial estimates of theta (0, 55.4) ; 1. Clearance (0, 2910) ; 2. Central volume of distribution (0, 310) ; 3. Inter-compartment clearance 1 (0, 4910) ; 4. Peripheral volume of distribution 1 (0, 105) ; 5. Inter-compartment clearance 2 (0, 30900) ; 6. Peripheral volume of distribution 2 (0, 2.11) ; 7. Mean transit time (1 FIX) ; 8. Relative bioavailability (0, 1.06) ; 9. Scaling factor (venous to capillary) (-1, 0.237) ; 10. Dose occasion on relative bioavailability (0, 0.575) ; 11. Age to reach 50% of full maturation (0, 5.51) ; 12. Hill coefficient $OMEGA ; Initial estimates for omega (0.075) ; 1. IIV clearance (0.371) ; 2. IIV central volume of distribution (0 FIX) ; 3. IIV Inter-compartment clearance 1 (0.056) ; 4. IIV peripheral volume of distribution 1 (0.054) ; 5. IIV inter-compartment clearance 2 (0.114) ; 6. IIV peripheral volume of distribution 2 (0.135) ; 7. IIV mean transit time (0.158) ; 8. IIV relative bioavailability $OMEGA BLOCK(1) 0.252 ; 9. IOV relative bioavailability $OMEGA BLOCK(1) SAME ;10. IOV relative bioavailability $OMEGA BLOCK(1) SAME ;11. IOV relative bioavailability $OMEGA BLOCK(1) 0.195 ; 12. IOV mean transit time $OMEGA BLOCK(1) SAME ; 13. IOV mean transit time $OMEGA BLOCK(1) SAME ; 14. IOV mean transit time $SIGMA ; Initial estimates of sigma (0.115) ; Residual variability $ESTIMATION POSTHOC MAXEVAL = 0 METHOD = 1 INTER $TABLE ID EVID TIME EVID IPRED AGE WT MAT OCC MDV IPRED CWRES PRED DV NOPRINT ONEHEADER FILE=mytab1_exemple