$SIZES NO=800 LIM6=800 ; needed for big datasets $PROBLEM Biomarker models for VEGF, VEGFR2, VEGFR3 and SKIT ; Reference: Hansson E.K. 2011. Pharmacometric models for Biomarkers, Side Effects and Efficacy in Anticancer Drug Therapy. Acta Universitatis Upsaliensis. $INPUT ID ; Patient identification CYCL ; Cycle number TIME ; Time in hours WEEK ; Time in weeks FLAG ; 1. Dose ; 4. Tumor size (SLD) (ignored) ; 5.VEGF ; 6.VEGFR2 ; 7.VEGFR3 ; 8. SKIT DVX ; DV on a linear scale DV ; log-transformed DV DOS ; Dose in mg PLA ; Placebo: 1. untreated, 0. treated CL ; posthoc total plasma clearance from a previously developed 2-compartment model EVID ; 0.PD assessment ; 2. other event $DATA data_ddmore_Biomarker_GIST_simulated.csv IGN=# ACCEPT(FLAG.EQ.1,FLAG.EQ.5,FLAG.EQ.6,FLAG.EQ.7,FLAG.EQ.8) $SUBROUTINE ADVAN6 TOL=5 $ABBR DERIV2=NOCOMMON $MODEL NCOMPS=4 COMP=COMP1 ;VEGF COMP=COMP2 ;sVEGFR-2 COMP=COMP3 ;sVEGFR-3 COMP=COMP4 ;SKIT $PK ; Verbatim code : changes the iteration maximum (IMAX) (default value 100000) "FIRST " COMMON /PRCOMG/ IDUM1,IDUM2,IMAX,IDUM4,IDUM5 " INTEGER IDUM1,IDUM2,IMAX,IDUM4,IDUM5 " IMAX=70000000 ;------VEGF------------------------------------ BM0 = THETA(1)*EXP(ETA(1)) ; Baseline VEGF MRT = THETA(2)*EXP(ETA(5)) IMAX1 = THETA(3) IC50 = THETA(4)*EXP(ETA(7)) ; Common IC50 for the four biomarkers which were found to be highly correlated HILL = THETA(5) ; Hill coefficient for VEGF sigmoid Imax model TVSLO = THETA(6)/1000 DPSLO = TVSLO *EXP(ETA(11)) ; Slope for the disease progression model ;------VEGFR2---------------------------------- BM02 = THETA(7)*EXP(ETA(2)) ; Baseline VEGFR2 MRT2 = THETA(8)*EXP(ETA(5)) IMAX2 = THETA(3) IC502 = THETA(4)*EXP(ETA(8)) HILL2 = THETA(9) ; Hill coefficient for VEGFR2 sigmoid IMAX model ;------VEGFR3---------------------------------- BM03 = THETA(10)*EXP(ETA(3)) ; Baseline VEGFR3 MRT3 = THETA(11)*EXP(ETA(5)) IMAX3 = THETA(3) IC503 = THETA(4)*EXP(ETA(9)) ;------SKIT------------------------------------ BM0S = THETA(12)*EXP(ETA(4)) ; Baseline SKIT MRTS = THETA(13)*EXP(ETA(6)) IMAXS = THETA(3) IC50S = THETA(4)*EXP(ETA(10)) TVSLOS = THETA(6)/1000 DPSLOS = TVSLOS *EXP(ETA(12)) ; Slope for the disease progression model ;------Compartment initialization-------------- A_0(1) = BM0 ; VEGF A_0(2) = BM02 ; sVEGFR-2 A_0(3) = BM03 ; sVEGFR-3 A_0(4) = BM0S ; sKIT KOUT = 1/MRT KOUT2 = 1/MRT2 KOUT3 = 1/MRT3 KOUTS = 1/MRTS KIN2 = BM02*KOUT2 KIN3 = BM03*KOUT3 AUC = DOS/CL DP1 = BM0*(1+DPSLO*TIME) ; Linear disease progression model for VEGF DPS = BM0S*(1+DPSLOS*TIME) ; Linear disease progression model for SKIT $DES ;-----PD: Sunitinib effect-------------------- KIN = DP1*KOUT KINS = DPS*KOUTS EFF = IMAX1*AUC**HILL /(IC50**HILL+AUC**HILL) ; VEGF : sigmoid Imax drug effect relationship EFF2 = IMAX2*AUC**HILL2/(IC502**HILL2+AUC**HILL2) ; VEGFR2: sigmoid Imax drug effect relationship EFF3 = IMAX3*AUC/(IC503+AUC) ; VEGFR3: Imax drug effect relationship EFFS = IMAXS*AUC/(IC50S+AUC) ; SKIT : Imax drug effect relationship DADT(1) = KIN-KOUT*(1-EFF)*A(1) ; VEGF : Inhibition of Kout DADT(2) = KIN2*(1-EFF2)-KOUT2*A(2) ; VEGFR2: Inhibition of Kin DADT(3) = KIN3*(1-EFF3)-KOUT3*A(3) ; VEGFR3: Inhibition of Kin DADT(4) = KINS*(1-EFFS)-KOUTS*A(4) ; SKIT : Inhibition of Kin $ERROR ;----- stratification for VPCs ---------- STRT=0 IF(FLAG.EQ.5.AND.PLA.EQ.0) STRT=1 ; VEGF, treatment IF(FLAG.EQ.5.AND.PLA.EQ.1) STRT=2 ; VEGF, placebo IF(FLAG.EQ.6) STRT=3 ; sVEGFR-2 IF(FLAG.EQ.7) STRT=4 ; sVEGFR-3 IF(FLAG.EQ.8.AND.PLA.EQ.0) STRT=5 ; sKIT, treatment IF(FLAG.EQ.8.AND.PLA.EQ.1) STRT=6 ; sKIT, placebo DEL=0 ; to avoid numerical problems IF(A(1).EQ.0)DEL=1 IF(A(2).EQ.0)DEL=1 IF(A(3).EQ.0)DEL=1 IF(A(4).EQ.0)DEL=1 IF(FLAG.EQ.5) THEN ; VEGF IPRED = LOG(A(1)+DEL) ; modeling performed on log transformed VEGF W = THETA(14) Y = IPRED+W*EPS(1) ENDIF IF(FLAG.EQ.6) THEN ; VEGFR2 IPRED = LOG(A(2)+DEL) ; modeling performed on log transformed VEGFR2 W = SQRT(THETA(15)**2+(THETA(16)/A(2))**2) Y = IPRED+W*EPS(1) END IF IF(FLAG.EQ.7) THEN ; VEGFR3 IPRED = LOG(A(3)+DEL) ; modeling performed on log transformed VEGFR3 W = THETA(17) Y = IPRED+W*EPS(1) ENDIF IF(FLAG.EQ.8) THEN ; SKIT IPRED = LOG(A(4)+DEL) ; modeling performed on log transformed SKIT W = THETA(18) Y = IPRED+W*EPS(1) ENDIF IF(W.EQ.0)W=1 IRES = DV - IPRED IWRES = IRES/W ;-----INITIAL ESTIMATES------------------------ ;-----VEGF------------------------------------- $THETA (0,59.7) ; 1 BM0 $THETA (0,91) ; 2 MRT $THETA 1 FIX ; 3 IMAX $THETA (0,1) ; 4 IC50 $THETA (0,3.31) ; 5 HILL $THETA (-0.06,0.035) ; 6 DP SLOPE ;-----VEGFR2----------------------------------- $THETA (0,8670) ; 7 BM02 $THETA (0,554) ; 8 MRT2 $THETA (0,1.54) ; 9 HILL2 ;-----VEGR3------------------------------------ $THETA (0,63900) ; 10 BM03 $THETA (0,401) ; 11 MRT3 ;-----SKIT------------------------------------- $THETA (0,39200) ; 12 BM0S $THETA (0,2430) ; 13 MRTS ;-----RES-------------------------------------- $THETA (0,0.445) ; 14 RES ERROR PROP $THETA (0,0.12) ; 15 RES VEGFR2 $THETA (0,583) ; 16 RES VEGFR2 $THETA (0,0.22) ; 17 RES VEGFR3 $THETA (0,0.224) ; 18 RES sKIT ;-----BM0------------------------------------- $OMEGA 0.252 ; 1 ETA BM0 $OMEGA 0.0369 ; 2 ETA BM02 $OMEGA 0.186 ; 3 ETA BM03 $OMEGA 0.254 ; 4 ETA BM0S ;-----MRT-------------------------------------- $OMEGA 0.0600 ; 5 ETA MRT sVEGFR-2,3 $OMEGA 0.0753 ; 6 ETA MRT sKIT ;-----IC50------------------------------------- $OMEGA BLOCK(4) 0.253 ; 7 ETA IC50 0.198 0.189 ; 8 ETA IC502 0.238 0.252 0.398 ; 9 ETA IC503 0.218 0.297 0.936 5.77 ; 10 ETA IC50S $OMEGA 2.95 ; 11 ETA DP SLOPE VEGF $OMEGA 3.01 ; 12 ETA DP SLOPE SKIT $SIGMA 1 FIX $EST SIGDIGITS=4 MAXEVALS=0 POSTHOC PRINT=1 MSFO=MSF1 METH=1 INTER ; FOCE with interaction ;$COV $TABLE ID CYCL EVID TIME PLA FLAG IPRED IWRES NOPRINT ONEHEADER FILE=sdtab1 $TABLE ID FLAG BM0 MRT IC50 DPSLO BM02 MRT2 IC502 BM03 MRT3 IC503 BM0S MRTS IC50S DPSLOS NOPRINT ONEHEADER FILE=patab1 $TABLE ID TIME PLA FLAG NOPRINT ONEHEADER FILE=catab1