;Model Desc: TDM1 ADC PK Model ;$Brendan C. Bender 12/16/2015 $SIZES PC=26 LTH=20 ; $PROB RUN# 100 ;******* ;----------------------------------------------------- ;Current RUN Notes: ;----------------------------------------------------- ; $INPUT C STUD=DROP SPEC SPC2 VITR DDAR DOSE PID=DROP ID WT IDAR TIME TAD AMT ODV=DROP DV NM=DROP CMT1=DROP CMT2=DROP CMT TYPE EVID MDV ZERO ONE TWO THRE FOUR FIVE SIX SEVE TDM TYP2 ;CMT 1=CENTRAL, 2=PERIPHERAL ;CMT 1 INITIALIZED WITH AMT=DOSE ; $DATA /blue/home/USER/brebe922/TDM1_DECONJUGATION/ddmore/Real_ADC_PK_Data.csv IGNORE=C IGN=(TIME.GT.28) $SUBROUTINE ADVAN6 TRANS1 TOL=3 $MODEL NCOMP=25 ; $PK ;------------------------------------------------------- ;PK MODEL PARAMETERS ;PK PARAMETER DECLARATION ; ; ;CL - Linear Clearance (L/kg/day) ;V1 - Central Volume (L/kg) ;CLd2 - Distributional Clearance 2 (L/kg/day) ;V2 - Peripheral volume 2 (L/kg) ;CLd3 - Distributional Clearance 3 (L/kg/day) ;V3 - Peripheral volume 3 (L/kg) ;------------------------------------------------------- ; KAB=THETA(1)*DEXP(ETA(1)); K10=THETA(2)*DEXP(ETA(2)); K21=THETA(3)*DEXP(ETA(3)); K32=THETA(4)*DEXP(ETA(4)); K43= K32 K54= K32 K65= K32 K76= K32 VTT=THETA(5)*DEXP(ETA(5)); CL= THETA(6)*DEXP(ETA(6)); V1=THETA(7)*DEXP(ETA(7)); CLd2=THETA(8)*DEXP(ETA(8)); V2= THETA(9)*DEXP(ETA(9)); CLd3=THETA(10)*DEXP(ETA(10)); V3= THETA(11)*DEXP(ETA(11)); VSS=V1+V2+V3 ; IF(VITR.EQ.1) THEN CL=0 CLd2=0 CLd3=0 V1=VTT SCLC=1 SCLV=1 ENDIF IF(VITR.EQ.0) THEN KAB=0 ENDIF S1=V1 S4=V1 S7=V1 S10=V1 S13=V1 S16=V1 S19=V1 S22=V1 ;Dose in ug................. F1=WT*SEVE*DOSE/100 F4=WT*SIX*DOSE/100 F7=WT*FIVE*DOSE/100 F10=WT*FOUR*DOSE/100 F13=WT*THRE*DOSE/100 F16=WT*TWO*DOSE/100 F19=WT*ONE*DOSE/100 F22=WT*ZERO*DOSE/100 ;Dose in pmol/kg................. ;F1=(SEVE*DOSE/100)*1000000/145167 $DES DADT(1)= -K76*A(1)-KAB*A(1)-(CL/V1+CLd2/V1+CLd3/V1)*A(1)+(CLd2/V2)*A(2)+(CLd3/V3)*A(3);DAR7 CENTRAL DADT(2)= (CLd2/V1)*A(1)-(CLd2/V2)*A(2) ;DAR7 PERIPHERAL DADT(3)= (CLd3/V1)*A(1)-(CLd3/V3)*A(3) ;DAR7 PERIPHERAL DADT(4)= K76*A(1)-K65*A(4)-KAB*A(4)-(CL/V1+CLd2/V1+CLd3/V1)*A(4)+(CLd2/V2)*A(5)+(CLd3/V3)*A(6);DAR6 CENTRAL DADT(5)= (CLd2/V1)*A(4)-(CLd2/V2)*A(5) ;DAR6 PERIPHERAL DADT(6)= (CLd3/V1)*A(4)-(CLd3/V3)*A(6) ;DAR6 PERIPHERAL DADT(7)= K65*A(4)-K54*A(7)-KAB*A(7)-(CL/V1+CLd2/V1+CLd3/V1)*A(7)+(CLd2/V2)*A(8)+(CLd3/V3)*A(9);DAR5 CENTRAL DADT(8)= (CLd2/V1)*A(7)-(CLd2/V2)*A(8) ;DAR5 PERIPHERAL DADT(9)= (CLd3/V1)*A(7)-(CLd3/V3)*A(9) ;DAR5 PERIPHERAL DADT(10)= K54*A(7)-K43*A(10)-KAB*A(10)-(CL/V1+CLd2/V1+CLd3/V1)*A(10)+(CLd2/V2)*A(11)+(CLd3/V3)*A(12);DAR4 CENTRAL DADT(11)= (CLd2/V1)*A(10)-(CLd2/V2)*A(11) ;DAR4 PERIPHERAL DADT(12)= (CLd3/V1)*A(10)-(CLd3/V3)*A(12) ;DAR4 PERIPHERAL DADT(13)= K43*A(10)-K32*A(13)-KAB*A(13)-(CL/V1+CLd2/V1+CLd3/V1)*A(13)+(CLd2/V2)*A(14)+(CLd3/V3)*A(15);DAR3 CENTRAL DADT(14)= (CLd2/V1)*A(13)-(CLd2/V2)*A(14) ;DAR3 PERIPHERAL DADT(15)= (CLd3/V1)*A(13)-(CLd3/V3)*A(15) ;DAR3 PERIPHERAL DADT(16)= K32*A(13)-K21*A(16)-KAB*A(16)-(CL/V1+CLd2/V1+CLd3/V1)*A(16)+(CLd2/V2)*A(17)+(CLd3/V3)*A(18);DAR2 CENTRAL DADT(17)= (CLd2/V1)*A(16)-(CLd2/V2)*A(17) ;DAR2 PERIPHERAL DADT(18)= (CLd3/V1)*A(16)-(CLd3/V3)*A(18) ;DAR2 PERIPHERAL DADT(19)= K21*A(16)-K10*A(19)-KAB*A(19)-(CL/V1+CLd2/V1+CLd3/V1)*A(19)+(CLd2/V2)*A(20)+(CLd3/V3)*A(21);DAR1 CENTRAL DADT(20)= (CLd2/V1)*A(19)-(CLd2/V2)*A(20) ;DAR1 PERIPHERAL DADT(21)= (CLd3/V1)*A(19)-(CLd3/V3)*A(21) ;DAR1 PERIPHERAL ; DADT(22)= K10*A(19) -KAB*A(22)-(CL/V1)*A(22);DAR0 CENTRAL DADT(22)= K10*A(19) -KAB*A(22)-(CL/V1+CLd2/V1+CLd3/V1)*A(22)+(CLd2/V2)*A(23)+(CLd3/V3)*A(24);DAR0 CENTRAL DADT(23)= (CLd2/V1)*A(22)-(CLd2/V2)*A(23) ;DAR0 PERIPHERAL DADT(24)= (CLd3/V1)*A(22)-(CLd3/V3)*A(24) ;DAR0 PERIPHERAL $ERROR TAB=(A(1)+A(4)+A(7)+A(10)+A(13)+A(16)+A(19)+A(22))/V1 TDM1=(A(1)+A(4)+A(7)+A(10)+A(13)+A(16)+A(19))/V1 TDM2=(A(1)+A(4)+A(7)+A(10)+A(13)+A(16))/V1 DM1T= (A(1)*7+A(4)*6+A(7)*5+A(10)*4+A(13)*3+A(16)*2+A(19)*1+A(22)*0) DAR= DM1T/(A(1)+A(4)+A(7)+A(10)+A(13)+A(16)+A(19)+A(22)) IPRE=LOG(F + 0.000001); IF (TYPE.EQ.1) IPRE=LOG(TAB) ; IF (TYPE.EQ.2) IPRE=LOG(TDM2) IRES=DV-IPRE; W=THETA(12) IF(W.EQ.0) W=1 IWRES=IRES/W; Y=IPRE + W*EPS(1); proportional error ICL= CL/WT; IV1= V1/WT; ICLd2= CLd2/WT; IV2= V2/WT; ICLd3= CLd3/WT; IV3= V3/WT; ; $THETA (0.01, 0.1); 1 KAB (0.01, 0.076);2 K10 (0.02, 0.26); 3 K21 (0.03, 0.3); 4 K32 (0.1, 1.03); 5 VTT (2, 16); 6 CL 30.0 (mL/day) (10, 100); 7 V1 (mL) (10, 100); 8 CLd2 (mL/day) (7, 70); 9 V2 (mL) (2, 20); 10 CLd3 (mL/day) (10, 100); 11 V3 (mL) (0, 0.201); 12 PROP ERR $OMEGA 0 FIX ; 1 KAB 0 FIX ; 2 K10 0 FIX ; 3 K21 0 FIX ; 4 K32 0 FIX ; 5 VTT 0.04 ; 6 CL 0.04 ; 7 V1 0 FIX ; 8 CLd2 0.2 ; 9 V2 0 FIX ; 10 CLd3 0 FIX ; 11 V3 ; $SIGMA 1 FIX ; ;$MSFI 100.MSF ;$EST METHOD=0 POSTHOC MAXEVAL=0 PRINT=20 $EST METHOD=1 INTERACTION MAXEVAL=9999 NOABORT PRINT=20 ; ;$SIMULATION (230) ONLY SUB=1 ; $COV ; $TABLE SPEC VITR DOSE DDAR ID IDAR TIME EVID CMT IPRE DV IWRES CWRES CL V1 CLd2 V2 CLd3 V3 VSS WT TYPE TAB TDM1 TDM2 DM1T DAR ICL IV1 ICLd2 IV2 ICLd3 IV3 ETA(1) ETA(2) ETA(3) ETA(4) ETA(7) ETA(8) ETA(9) ETA(10) ETA(11) NOPRINT ONEHEADER FILE=tdm1_dec_1.TAB ; ;END .CTL