;PKPD Workshop
;Control Streams
;Nick Holford
;Dept Pharmacology & Clinical Pharmacology
;University of Auckland
$PROB Warfarin PKPD KA1
;O'Reilly RA, Aggeler PM, Leong LS. Studies of the coumarin anticoagulant
;drugs: The pharmacodynamics of warfarin in man.
;Journal of Clinical Investigation 1963;42(10):1542-1551
;O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs
;Initiation of warfarin therapy without a loading dose.
;Circulation 1968;38:169-177
$DATA conc_No12.csv
$INPUT ID time wt age sex amt dvid dv mdv
$EST MAX=9990 SIG=3 PRINT=20 NOABORT
METHOD=COND INTER 
$COV
$THETA
(0.01,0.134,1) ; POPCL L/h/70kg
(0.01,8.1,20) ; POPV L/70kg
(0.01,0.523,24) ; POPTABS h
(0.01,0.822,24) ; POPLAG h
$OMEGA
0.0713 ; PPVCL
0.0181 ; PPVV
0.696 ; PPVTABS
0.156 ; PPVLAG
$SIGMA 0.00752 ; RUVCV
$SIGMA 0.0661 ; RUVSD mg/L
$SUBR ADVAN2 TRAN2
$PK
IF (NEWIND.LE.1) LN2=LOG(2)
FSZV=WT/70
FSZCL=FSZV**0.75
CL=FSZCL*POPCL*EXP(PPVCL)
V=FSZV*POPV*EXP(PPVV)
TABS=POPTABS*EXP(PPVTABS)
TLAG=POPLAG*EXP(PPVLAG)
KA=LN2/TABS
ALAG1=TLAG
S2=V
$ERROR
CP=F
Y=CP*(1+RUVCV) + RUVSD
$TABLE ID TIME DVID Y
ONEHEADER NOPRINT FILE=ka1.fit
$PROB Warfarin PKPD Ka1_blk
;O'Reilly RA, Aggeler PM, Leong LS. Studies of the coumarin anticoagulant
;drugs: The pharmacodynamics of warfarin in man.
;Journal of Clinical Investigation 1963;42(10):1542-1551
;O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs
;Initiation of warfarin therapy without a loading dose.
;Circulation 1968;38:169-177
$DATA conc_No12.csv
$INPUT ID time wt age sex amt dvid dv mdv
$EST MAX=9990 SIG=3 PRINT=20 NOABORT
METHOD=COND INTER 
$COV
$THETA
(0.01,0.134,1) ; POPCL L/h/70kg
(0.01,8.1,20) ; POPV L/70kg
(0.01,0.366,24) ; POPTABS h
(0.01,0.942,24) ; POPLAG h
$OMEGA BLOCK(4)
0.0712 ; PPVCL
0.00629 0.0179 ; PPVV
0.0572 -0.0401 1.14 ; PPVTABS
-0.0319 -0.00916 -0.0808 0.116 ; PPVLAG
$SIGMA 0.00765 ; RUVCV
$SIGMA 0.0614 ; RUVSD mg/L
$SUBR ADVAN2 TRAN2
$PK
IF (NEWIND.LE.1) LN2=LOG(2)
FSZV=WT/70
FSZCL=FSZV**0.75
CL=FSZCL*POPCL*EXP(PPVCL)
V=FSZV*POPV*EXP(PPVV)
TABS=POPTABS*EXP(PPVTABS)
TLAG=POPLAG*EXP(PPVLAG)
KA=LN2/TABS
ALAG1=TLAG
S2=V
$ERROR
CP=F
Y=CP*(1+RUVCV) + RUVSD
$TABLE ID TIME DVID Y
ONEHEADER NOPRINT FILE=ka1.fit
$PROB Warfarin PKPD ka1_ce_ADVAN4
;O'Reilly RA, Aggeler PM, Leong LS. Studies of the coumarin anticoagulant
;drugs: The pharmacodynamics of warfarin in man.
;Journal of Clinical Investigation 1963;42(10):1542-1551
;O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs
;Initiation of warfarin therapy without a loading dose.
;Circulation 1968;38:169-177
$DATA conc_pcaNo12.csv
$INPUT ID time wt age sex amt dvid dv mdv
$EST MAX=9990 SIG=3 PRINT=20 
METHOD=COND INTER 
$COV
$THETA
(0.01,0.134,1) ; POPCL L/h/70kg
(0.01,8.1,20) ; POPV L/70kg
(0.01,0.523,24) ; POPTABS h
(0.01,0.822,24) ; POPLAG h
(0.01,75.6,200) ; POPE0
(-INF,-237.,0) ; POPEMAX
(0.01,10.,100) ; POPC50
(0.01,37.4,100) ; POPTEQ
$OMEGA
0.0713 ; PPVCL
0.0181 ; PPVV
0.696 ; PPVTABS
0.339 ; PPVLAG
0.0627 ; PPVE0
0.05 ; PPVEMAX
0.0564 ; PPVC50
0.0731 ; PPVTEQ
$SIGMA 
0.00752 ; RUVCV
0.0661 ; RUVSD mg/L
14.6 ; RUVFX
$SUBR ADVAN4 TRAN4
$PK
IF (NEWIND.LE.1) LN2=LOG(2)
FSZV=WT/70
FSZCL=FSZV**0.75
CL=FSZCL*POPCL*EXP(PPVCL)
V=FSZV*POPV*EXP(PPVV)
TABS=POPTABS*EXP(PPVTABS)
TLAG=POPLAG*EXP(PPVLAG)
E0=POPE0*EXP(PPVE0)
EMAX=POPEMAX*EXP(PPVEMAX)
C50=POPC50*EXP(PPVC50)
TEQ=POPTEQ*EXP(PPVTEQ)
KEQ=LN2/TEQ
KA=LN2/TABS
ALAG1=TLAG
S2=V
V2=V
V3=V2*0.0001
Q=V3*KEQ
$ERROR
CP=F
CE=A(3)/V3
PCA=E0 + EMAX*CE/(C50+CE)
IF (DVID.LE.1) THEN
Y=CP*(1+RUVCV) + RUVSD
ENDIF
IF (DVID.EQ.2) THEN
Y=PCA + RUVFX
ENDIF
$TABLE ID TIME DVID CP CE PCA Y
ONEHEADER NOPRINT FILE=ka1.fit
$PROB Warfarin PKPD Ka1_ce_ADVAN6
;O'Reilly RA, Aggeler PM, Leong LS. Studies of the coumarin anticoagulant
;drugs: The pharmacodynamics of warfarin in man.
;Journal of Clinical Investigation 1963;42(10):1542-1551
;O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs
;Initiation of warfarin therapy without a loading dose.
;Circulation 1968;38:169-177
$DATA conc_pcaNo12.csv
$INPUT ID time wt age sex amt dvid dv mdv
$EST MAX=9990 SIG=3 PRINT=20 NOABORT
METHOD=COND INTER 
$COV
$THETA
(0.01,0.134,1) ; POPCL L/h/70kg
(0.01,8.1,20) ; POPV L/70kg
(0.01,0.523,24) ; POPTABS h
(0.01,0.822,24) ; POPLAG h
(0.01,75.6,200) ; POPE0
(-INF,-257.,0) ; POPEMAX
(0.01,10.,100) ; POPC50
(0.01,37.4,100) ; POPTEQ
$OMEGA
0.0713 ; PPVCL
0.0181 ; PPVV
0.696 ; PPVTABS
0.339 ; PPVLAG
0.0627 ; PPVE0
0.05 ; PPVEMAX
0.0564 ; PPVC50
0.0731 ; PPVTEQ
$SIGMA 
0.00752 ; RUVCV
0.0661 ; RUVSD mg/L
14.6 ; RUVFX
$SUBR ADVAN6 TOL=3
$MODEL
COMP (DEPOT)
COMP (CENTRAL)
COMP (EFFECT)
$PK
IF (NEWIND.LE.1) LN2=LOG(2)
FSZV=WT/70
FSZCL=FSZV**0.75
CL=FSZCL*POPCL*EXP(PPVCL)
V=FSZV*POPV*EXP(PPVV)
TABS=POPTABS*EXP(PPVTABS)
TLAG=POPLAG*EXP(PPVLAG)
E0=POPE0*EXP(PPVE0)
EMAX=POPEMAX*EXP(PPVEMAX)
C50=POPC50*EXP(PPVC50)
TEQ=POPTEQ*EXP(PPVTEQ)
KEQ=LN2/TEQ
KA=LN2/TABS
ALAG1=TLAG
S2=V
$DES
GUT=A(1)
DCP=A(2)/V
DCE=A(3)
RATEIN=KA*GUT
DADT(1)= -RATEIN
DADT(2)= RATEIN - DCP*CL
DADT(3)= KEQ*(DCP - DCE)
$ERROR
CP=A(2)/V
CE=A(3)
PCA=E0 + EMAX*CE/(C50+CE)
IF (DVID.LE.1) THEN
Y=CP*(1+RUVCV) + RUVSD
ENDIF
IF (DVID.EQ.2) THEN
Y=PCA + RUVFX
ENDIF
$TABLE ID TIME DVID CP CE PCA Y
ONEHEADER NOPRINT FILE=ka1.fit
$PROB Warfarin PKPD Ka1_ce_PRED
;O'Reilly RA, Aggeler PM, Leong LS. Studies of the coumarin anticoagulant
;drugs: The pharmacodynamics of warfarin in man.
;Journal of Clinical Investigation 1963;42(10):1542-1551
;O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs
;Initiation of warfarin therapy without a loading dose.
;Circulation 1968;38:169-177
$DATA conc_pcaNo12.csv
$INPUT ID time wt age sex amt dvid dv mdv
$EST MAX=9990 SIG=3 PRINT=20 
METHOD=COND INTER 
$COV
$THETA
(0.01,0.134,1) ; POPCL L/h/70kg
(0.01,8.1,20) ; POPV L/70kg
(0.01,0.523,24) ; POPTABS h
(0.01,0.822,24) ; POPLAG h
(0.01,75.6,200) ; POPE0
(-INF,-237.,0) ; POPEMAX
(0.01,10.,100) ; POPC50
(0.01,37.4,100) ; POPTEQ
$OMEGA
0.0713 ; PPVCL
0.0181 ; PPVV
0.696 ; PPVTABS
0.339 ; PPVLAG
0.0627 ; PPVE0
0.05 ; PPVEMAX
0.0564 ; PPVC50
0.0731 ; PPVTEQ
$SIGMA 
0.00752 ; RUVCV
0.0661 ; RUVSD mg/L
14.6 ; RUVFX
$PRED
IF (NEWIND.LE.1) THEN
LN2=LOG(2)
DOSE=0
ENDIF
IF (AMT.GT.0) DOSE=AMT
FSZV=WT/70
FSZCL=FSZV**0.75
CL=FSZCL*POPCL*EXP(PPVCL)
V=FSZV*POPV*EXP(PPVV)
TABS=POPTABS*EXP(PPVTABS)
TLAG=POPLAG*EXP(PPVLAG)
E0=POPE0*EXP(PPVE0)
EMAX=POPEMAX*EXP(PPVEMAX)
C50=POPC50*EXP(PPVC50)
TEQ=POPTEQ*EXP(PPVTEQ)
KEQ=LN2/TEQ
KA=LN2/TABS
KE=CL/V
IF (TIME.LE.TLAG) THEN
TNOW=0
ELSE
TNOW=TIME-TLAG
ENDIF
EXPKA=EXP(-KA*TNOW)
EXPKE=EXP(-KE*TNOW)
EXPKQ=EXP(-KEQ*TNOW)
CP=DOSE*KA/(V*(KA-KE))*(EXPKE-EXPKA)
CEEXKE=EXPKE/(KA-KE)/(KEQ-KE)
CEEXKA=EXPKA/(KE-KA)/(KEQ-KA)
CEEXKQ=EXPKQ/(KA-KEQ)/(KE-KEQ)
CE=DOSE*KA*KEQ/V*(CEEXKE+CEEXKA+CEEXKQ)
PCA=E0 + EMAX*CE/(C50+CE)
IF (DVID.LE.1) THEN
Y=CP*(1+RUVCV) + RUVSD
ENDIF
IF (DVID.EQ.2) THEN
Y=PCA + RUVFX
ENDIF
$TABLE ID TIME DVID CP CE PCA Y
ONEHEADER NOPRINT FILE=ka1.fit
$PROB Warfarin PKPD Ka1_im_ADVAN2
;O'Reilly RA, Aggeler PM, Leong LS. Studies of the coumarin anticoagulant
;drugs: The pharmacodynamics of warfarin in man.
;Journal of Clinical Investigation 1963;42(10):1542-1551
;O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs
;Initiation of warfarin therapy without a loading dose.
;Circulation 1968;38:169-177
$DATA conc_pcaNo12.csv
$INPUT ID time wt age sex amt dvid dv mdv
$EST MAX=9990 SIG=3 PRINT=20 
METHOD=COND INTER 
$COV
$THETA
(0.01,0.134,1) ; POPCL L/h/70kg
(0.01,8.1,20) ; POPV L/70kg
(0.01,0.523,24) ; POPTABS h
(0.01,0.822,24) ; POPLAG h
(0.01,49.1,200) ; POPE0
(-INF,-120.,0) ; POPEMAX
(0.01,7.76,100) ; POPC50
$OMEGA
0.0713 ; PPVCL
0.0181 ; PPVV
0.696 ; PPVTABS
0.156 ; PPVLAG
0.709 ; PPVE0
1. ; PPVEMAX
1.07 ; PPVC50
$SIGMA 0.00752 ; RUVCV
$SIGMA 0.0661 ; RUVSD mg/L
$SIGMA 694. ; RUVFX
$SUBR ADVAN2 TRAN2
$PK
IF (NEWIND.LE.1) LN2=LOG(2)
FSZV=WT/70
FSZCL=FSZV**0.75
CL=FSZCL*POPCL*EXP(PPVCL)
V=FSZV*POPV*EXP(PPVV)
TABS=POPTABS*EXP(PPVTABS)
TLAG=POPLAG*EXP(PPVLAG)
KA=LN2/TABS
ALAG1=TLAG
S2=V
E0=POPE0*EXP(PPVE0)
EMAX=POPEMAX*EXP(PPVEMAX)
C50=POPC50*EXP(PPVC50)
DLTA=E0+EMAX
; IF (DLTA.LT.0) EXIT 1 101
$ERROR
CP=F
PCA=E0 + EMAX*CP/(C50+CP)
IF (DVID.LE.1) THEN
Y=CP*(1+RUVCV) + RUVSD
ENDIF
IF (DVID.EQ.2) THEN
Y=PCA + RUVFX
ENDIF
$TABLE ID TIME DVID CP PCA Y
ONEHEADER NOPRINT FILE=ka1.fit
$PROB Warfarin PKPD Ka1_im_ADVAN6
;O'Reilly RA, Aggeler PM, Leong LS. Studies of the coumarin anticoagulant
;drugs: The pharmacodynamics of warfarin in man.
;Journal of Clinical Investigation 1963;42(10):1542-1551
;O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs
;Initiation of warfarin therapy without a loading dose.
;Circulation 1968;38:169-177
$DATA conc_pcaNo12.csv
$INPUT ID time wt age sex amt dvid dv mdv
$EST MAX=9990 SIG=3 PRINT=20 NOABORT
METHOD=COND INTER 
$COV
$THETA
(0.01,0.134,1) ; POPCL L/h/70kg
(0.01,8.1,20) ; POPV L/70kg
(0.01,0.523,24) ; POPTABS h
(0.01,0.822,24) ; POPLAG h
(0.01,75.6,200) ; POPE0
(-INF,-257.,0) ; POPEMAX
(0.01,10.,100) ; POPC50
$OMEGA
0.0713 ; PPVCL
0.0181 ; PPVV
0.696 ; PPVTABS
0.339 ; PPVLAG
0.0627 ; PPVE0
0.05 ; PPVEMAX
0.0564 ; PPVC50
$SIGMA 
0.00752 ; RUVCV
0.0661 ; RUVSD mg/L
14.6 ; RUVFX
$SUBR ADVAN6 TOL=3
$MODEL
COMP (DEPOT)
COMP (CENTRAL)
$PK
IF (NEWIND.LE.1) LN2=LOG(2)
FSZV=WT/70
FSZCL=FSZV**0.75
CL=FSZCL*POPCL*EXP(PPVCL)
V=FSZV*POPV*EXP(PPVV)
TABS=POPTABS*EXP(PPVTABS)
TLAG=POPLAG*EXP(PPVLAG)
E0=POPE0*EXP(PPVE0)
EMAX=POPEMAX*EXP(PPVEMAX)
C50=POPC50*EXP(PPVC50)
KA=LN2/TABS
ALAG1=TLAG
S2=V
$DES
GUT=A(1)
DCP=A(2)/V
RATEIN=KA*GUT
DADT(1)= -RATEIN
DADT(2)= RATEIN - DCP*CL
$ERROR
CP=A(2)/V
CE=CP
PCA=E0 + EMAX*CE/(C50+CE)
IF (DVID.LE.1) THEN
Y=CP*(1+RUVCV) + RUVSD
ENDIF
IF (DVID.EQ.2) THEN
Y=PCA + RUVFX
ENDIF
$TABLE ID TIME DVID CP CE PCA Y
ONEHEADER NOPRINT FILE=ka1.fit
$PROB Warfarin PKPD Ka1_im_PRED
;O'Reilly RA, Aggeler PM, Leong LS. Studies of the coumarin anticoagulant
;drugs: The pharmacodynamics of warfarin in man.
;Journal of Clinical Investigation 1963;42(10):1542-1551
;O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs
;Initiation of warfarin therapy without a loading dose.
;Circulation 1968;38:169-177
$DATA conc_pcaNo12.csv
$INPUT ID time wt age sex amt dvid dv mdv
$EST MAX=9990 SIG=3 PRINT=20 
METHOD=COND INTER 
$COV
$THETA
(0.01,0.134,1) ; POPCL L/h/70kg
(0.01,8.1,20) ; POPV L/70kg
(0.01,0.523,24) ; POPTABS h
(0.01,0.822,24) ; POPLAG h
(0.01,75.6,200) ; POPE0
(-INF,-237.,0) ; POPEMAX
(0.01,10.,100) ; POPC50
$OMEGA
0.0713 ; PPVCL
0.0181 ; PPVV
0.696 ; PPVTABS
0.339 ; PPVLAG
0.0627 ; PPVE0
0.05 ; PPVEMAX
0.0564 ; PPVC50
$SIGMA 
0.00752 ; RUVCV
0.0661 ; RUVSD mg/L
14.6 ; RUVFX
$PRED
IF (NEWIND.LE.1) THEN
LN2=LOG(2)
DOSE=0
ENDIF
IF (AMT.GT.0) DOSE=AMT
FSZV=WT/70
FSZCL=FSZV**0.75
CL=FSZCL*POPCL*EXP(PPVCL)
V=FSZV*POPV*EXP(PPVV)
TABS=POPTABS*EXP(PPVTABS)
TLAG=POPLAG*EXP(PPVLAG)
E0=POPE0*EXP(PPVE0)
EMAX=POPEMAX*EXP(PPVEMAX)
C50=POPC50*EXP(PPVC50)
KA=LN2/TABS
KE=CL/V
IF (TIME.LE.TLAG) THEN
TNOW=0
ELSE
TNOW=TIME-TLAG
ENDIF
EXPKA=EXP(-KA*TNOW)
EXPKE=EXP(-KE*TNOW)
CP=DOSE*KA/(V*(KA-KE))*(EXPKE-EXPKA)
CE=CP
PCA=E0 + EMAX*CE/(C50+CE)
IF (DVID.LE.1) THEN
Y=CP*(1+RUVCV) + RUVSD
ENDIF
IF (DVID.EQ.2) THEN
Y=PCA + RUVFX
ENDIF
$TABLE ID TIME DVID CP CE PCA Y
ONEHEADER NOPRINT FILE=ka1.fit
$PROB Warfarin PKPD Ka1_to_Emax1_ADVAN6
;O'Reilly RA, Aggeler PM, Leong LS. Studies of the coumarin anticoagulant
;drugs: The pharmacodynamics of warfarin in man.
;Journal of Clinical Investigation 1963;42(10):1542-1551
;O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs
;Initiation of warfarin therapy without a loading dose.
;Circulation 1968;38:169-177
$DATA conc_pca_to_No12.csv
$INPUT ID time wt age sex cmt amt dvid dv mdv
$EST MAX=9990 SIG=3 PRINT=20 
METHOD=COND INTER NOABORT
$COV
$THETA
(0.01,0.134,1) ; POPCL L/h/70kg
(0.01,8.1,20) ; POPV L/70kg
(0.01,0.523,24) ; POPTABS h
(0.01,0.822,24) ; POPLAG h
(0.01,96.5,200) ; POPE0
(-1,-1,0) FIX ; POPEMAX
(0.01,1.18,10) ; POPC50
(0.01,13.,100) ; POPTEQ
$OMEGA
0.0713 ; PPVCL
0.0181 ; PPVV
0.696 ; PPVTABS
0.156 ; PPVLAG
0.00288 ; PPVE0
0 FIX ; PPVEMAX
0.194 ; PPVC50
0.00214 ; PPVTEQ
$SIGMA 0.00752 ; RUVCV
$SIGMA 0.0661 ; RUVSD mg/L
$SIGMA 16.3 ; RUVFX
$SUBR ADVAN6 TOL=3
$MODEL
COMP=GUT
COMP=CENTRAL
COMP=PCA
$PK
IF (NEWIND.LE.1) LN2=LOG(2)
FSZV=WT/70
FSZCL=FSZV**0.75
CL=FSZCL*POPCL*EXP(PPVCL)
V=FSZV*POPV*EXP(PPVV)
TABS=POPTABS*EXP(PPVTABS)
TLAG=POPLAG*EXP(PPVLAG)
E0=POPE0*EXP(PPVE0)
EMAX=POPEMAX*EXP(PPVEMAX)
C50=POPC50*EXP(PPVC50)
TEQ=POPTEQ*EXP(PPVTEQ)
IF (EMAX.LT.-1) EXIT 1 101
KA=LN2/TABS
ALAG1=TLAG
S2=V
F3=E0
KPCA=LN2/TEQ
RPCA=E0*KPCA
$DES
RATEIN=KA*A(1)
DCP=A(2)/V
DPCA=A(3)
PD=1+EMAX*DCP/(C50+DCP)
DADT(1)=-RATEIN
DADT(2)=RATEIN - CL*DCP
DADT(3)=RPCA*PD - KPCA*DPCA
$ERROR
CP=A(2)/V
PCA=A(3)
IF (DVID.LE.1) THEN
Y=CP*(1+RUVCV) + RUVSD
ENDIF
IF (DVID.EQ.2) THEN
Y=PCA + RUVFX
ENDIF
$TABLE ID TIME DVID CP PCA Y
ONEHEADER NOPRINT FILE=ka1.fit
$PROB Warfarin PKPD Ka1_to_ADVAN6
;O'Reilly RA, Aggeler PM, Leong LS. Studies of the coumarin anticoagulant
;drugs: The pharmacodynamics of warfarin in man.
;Journal of Clinical Investigation 1963;42(10):1542-1551
;O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs
;Initiation of warfarin therapy without a loading dose.
;Circulation 1968;38:169-177
$DATA conc_pca_to_No12.csv
$INPUT ID time wt age sex cmt amt dvid dv mdv
$EST MAX=9990 SIG=3 PRINT=20 
METHOD=COND INTER NOABORT
$COV
$THETA
(0.01,0.134,1) ; POPCL L/h/70kg
(0.01,8.1,20) ; POPV L/70kg
(0.01,0.523,24) ; POPTABS h
(0.01,0.822,24) ; POPLAG h
(0.01,96.5,200) ; POPE0
(-1,-.9,0) ; POPEMAX
(0.01,1.18,10) ; POPC50
(0.01,13.,100) ; POPTEQ
$OMEGA
0.0713 ; PPVCL
0.0181 ; PPVV
0.696 ; PPVTABS
0.156 ; PPVLAG
0.00288 ; PPVE0
0.001 ; PPVEMAX
0.194 ; PPVC50
0.00214 ; PPVTEQ
$SIGMA 0.00752 ; RUVCV
$SIGMA 0.0661 ; RUVSD mg/L
$SIGMA 16.3 ; RUVFX
$SUBR ADVAN6 TOL=3
$MODEL
COMP=GUT
COMP=CENTRAL
COMP=PCA
$PK
IF (NEWIND.LE.1) LN2=LOG(2)
FSZV=WT/70
FSZCL=FSZV**0.75
CL=FSZCL*POPCL*EXP(PPVCL)
V=FSZV*POPV*EXP(PPVV)
TABS=POPTABS*EXP(PPVTABS)
TLAG=POPLAG*EXP(PPVLAG)
E0=POPE0*EXP(PPVE0)
EMAX=POPEMAX*EXP(PPVEMAX)
C50=POPC50*EXP(PPVC50)
TEQ=POPTEQ*EXP(PPVTEQ)
IF (EMAX.LT.-1) EXIT 1 101
KA=LN2/TABS
ALAG1=TLAG
S2=V
F3=E0
KPCA=LN2/TEQ
RPCA=E0*KPCA
$DES
RATEIN=KA*A(1)
DCP=A(2)/V
DPCA=A(3)
PD=1+EMAX*DCP/(C50+DCP)
DADT(1)=-RATEIN
DADT(2)=RATEIN - CL*DCP
DADT(3)=RPCA*PD - KPCA*DPCA
$ERROR
CP=A(2)/V
PCA=A(3)
IF (DVID.LE.1) THEN
Y=CP*(1+RUVCV) + RUVSD
ENDIF
IF (DVID.EQ.2) THEN
Y=PCA + RUVFX
ENDIF
$TABLE ID TIME DVID CP PCA Y
ONEHEADER NOPRINT FILE=ka1.fit