;; 1. Based on: 249 $PROBLEM 2-comp,allometric scaling,IOV on CL and V $INPUT ID DAT2=DROP OTIM=DROP TIME DV AMT RATE AGE WT BLGR PREP EVID OCC YBIN OCC2 STUD $DATA ../Data_FVIII_simulation.csv IGNORE=@ IGNORE=(STUD.EQ.1) $SUBROUTINE ADVAN3 TRANS4 $PK Q1 = 0 Q2 = 0 Q3 = 0 Q4 = 0 Q5 = 0 Q6 = 0 Q7 = 0 Q8 = 0 IF(OCC.EQ.1)Q1 = 1 IF(OCC.EQ.2)Q2 = 1 IF(OCC.EQ.3)Q3 = 1 IF(OCC.EQ.4)Q4 = 1 IF(OCC.EQ.5)Q5 = 1 IF(OCC.EQ.6)Q6 = 1 IF(OCC.EQ.7)Q7 = 1 IF(OCC.EQ.8)Q8 = 1 IF (PREP.EQ.1) PREP2 = 1 IF (PREP.EQ.2) PREP2 = 2 IF (PREP.EQ.3) PREP2 = 1 IF (PREP.EQ.4) PREP2 = 1 IF (PREP.EQ.5) PREP2 = 1 IF (PREP.EQ.6) PREP2 = 2 IF (PREP.EQ.7) PREP2 = 2 ;IF (PREP.EQ.8) PREP2 = 3 IF (PREP.EQ.9) PREP2 = 2 IF (PREP2.EQ.1) THEN TVCL = THETA(1)*((WT/68)**THETA(7))*(1+THETA(13)*(AGE-24)) ;68 = Median of body weight TVV1 = THETA(2)*((WT/68)**THETA(8)) ENDIF IF (PREP2.EQ.2) THEN TVCL = THETA(1)*((WT/68)**THETA(7))*(1+THETA(12))*(1+THETA(13)*(AGE-24)) TVV1 = THETA(2)*((WT/68)**THETA(8))*(1+THETA(12)) ENDIF TVQ = THETA(5)*(WT/68)**THETA(9) TVV2 = THETA(6)*(WT/68)**THETA(10) IOVCL= Q1*ETA(4)+Q2*ETA(5)+Q3*ETA(6)+Q4*ETA(7)+Q5*ETA(8) IOVCL2 = IOVCL+Q6*ETA(9)+Q7*ETA(10)+Q8*ETA(11) IOVV = Q1*ETA(12)+Q2*ETA(13)+Q3*ETA(14)+Q4*ETA(15) IOVV2= IOVV+Q5*ETA(16)+Q6*ETA(17)+Q7*ETA(18)+Q8*ETA(19) CL = TVCL*EXP(ETA(2)+IOVCL2) V1 = TVV1*EXP(ETA(3)+IOVV2) Q = TVQ V2 = TVV2 TVBA = THETA(11) BASE = TVBA*EXP(ETA(1)) S1 = V1 K = CL/V1 K12 = Q/V1 K21 = Q/V2 $ERROR IPRED = F + BASE IRES = DV-IPRED W = SQRT(THETA(3)**2 + (THETA(4)*IPRED)**2) IWRES = IRES/W ;IF(W.EQ.0) W = 1 Y = IPRED + W*EPS(1) $THETA (0,222) ; 1 CL (ml/h) $THETA (0,3520) ; 2 V1 (ml) $THETA (0,0.0121) ; 3 Add res error (SD,units = U/ml) $THETA (0,0.085) ; 4 Prop res error (Rel SD = CV) $THETA (0,256) ; 5 Q (ml/h) $THETA (0,241) ; 6 V2 (ml) $THETA 0.75 FIX ; 7 Scaling for CL $THETA 1 FIX ; 8 Scaling for V1 $THETA 0.75 FIX ; 9 Scaling for Q $THETA 1 FIX ; 10 Scaling for V2 $THETA (0,0.0124) ; 11 Baseline $THETA -0.201 ; 12 Difference in TVCL and TVV1 for full-lenght recombinant FVIII $THETA (-0.0185,-0.00695,0.055) ; 13 Fractional change in CL per year different from 24 years $OMEGA BLOCK(3) 0.0973 ; varBase 0.0476 0.0757 ; covarBase-CL varETACL 0 0.0298 0.0286 ; covar Base-V1, covar CL-V1, varV1 $OMEGA BLOCK(1) 0.0178 ; IOV for CL $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) 0.0109 ; IOV for V $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME $OMEGA BLOCK(1) SAME $SIGMA 1 FIX $ESTIMATION METHOD=1 INTER PRINT=1 MAXEVAL=0 ;$COVARIANCE