ADAPT-5 Code for Model in Figure-2

ADAPT-5 code for model in Figure-2

**********************************************************************

C ADAPT *

C Version 5 *

C**********************************************************************

C *

C MODEL *

C *

C This file contains Fortran subroutines into which the user *

C must enter the relevant model equations and constants. *

C Consult the User's Guide for details concerning the format for *

C entered equations and definition of symbols. *

C *

C 1. Symbol- Parameter symbols and model constants *

C 2. DiffEq- System differential equations *

C 3. Output- System output equations *

C 4. Varmod- Error variance model equations *

C 5. Covmod- Covariate model equations (ITS,MLEM) *

C 6. Popinit- Population parameter initial values (ITS,MLEM) *

C 7. Prior - Parameter mean and covariance values (ID,NPD,STS) *

C 8. Sparam- Secondary parameters *

C 9. Amat - System state matrix *

C *

C**********************************************************************

C######################################################################C

Subroutine SYMBOL

Implicit None

Include 'globals.inc'

Include 'model.inc'

C------C

C Enter as Indicated C

C----c------C

NDEqs = 3 ! Enter # of Diff. Eqs.

NSParam = 6 ! Enter # of System Parameters.

NVparam = 2 ! Enter # of Variance Parameters.

NSecPar = 1 ! Enter # of Secondary Parameters.

NSecOut = 0 ! Enter # of Secondary Outputs (not used).

Ieqsol = 1 ! Model type: 1 - DIFFEQ, 2 - AMAT, 3 - OUTPUT only.

Descr = ' Minimal-PBPK with two tissue compartments '

C------C

C Enter Symbol for Each System Parameter (eg. Psym(1)='Kel') C

C----c------C

Psym(1)='f1'

Psym(2)='f2'

Psym(3)='Kp1'

Psym(4)='Kp2'

Psym(5)='CL'

Psym(6)='V1'

C------C

C Enter Symbol for Each Variance Parameter {eg: PVsym(1)='Sigma'} C

C----c------C

PVsym(1)='intercept'

PVsym(2)='slope'

C------C

C Enter Symbol for Each Secondary Parameter {eg: PSsym(1)='CLt'} C

C----c------C

PSsym(1)='Vss'

C------C

Return

End

C######################################################################C

Subroutine DIFFEQ(T,X,XP)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Real*8 T,X(MaxNDE),XP(MaxNDE),Qco,Kp1,Kp2,f1,f2,V1,V2,Vp,BW,CL,f

Real*8 ECF

C------C

C Enter Differential Equations Below {e.g. XP(1) = -P(1)*X(1) } C

C----c------C

f1 = P(1)

f2 = P(2)

Kp1 = P(3)

Kp2 = P(4)

CL = P(4)

V1 = P(5)

CC----ECF is Extracelluar fluid------

ECF = 18.200

V2 = ECF-V1-Vp

CC----Cp is blood concentration---

Vp = 5.200

BW = 70

cc----Oco is cardiac output------

Qco = 5.600

f = f1+f2

c----blood compartment-----

IF(f .gt. 1) then

XP(1) = 0

else

XP(1) = R(1)+ f1*Qco*X(2)/Kp1 + f2*Qco*X(3)/Kp2 -

c (f1*Qco+f2*Qco+CL)*X(1)/Vp

endif

c----Tissue Compartment 1------

XP(2) = (f1*Qco*X(1)/Vp - f1*Qco* X(2)/Kp1)/V1

c----Tissue Compartment 2-----

XP(3) = (f2*Qco*X(1)/Vp - f2*Qco* X(3)/Kp2)/V2

C------C

Return

End

C######################################################################C

Subroutine OUTPUT(Y,T,X)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Real*8 Y(MaxNOE),T,X(MaxNDE),Vp

C------C

C Enter Output Equations Below {e.g. Y(1) = X(1)/P(2) } C

C----c------C

Vp = 5.200

Y(1) = X(1)/Vp

C------C

Return

End

C######################################################################C

Subroutine VARMOD(V,T,X,Y)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Real*8 V(MaxNOE),T,X(MaxNDE),Y(MaxNOE)

C------C

C Enter Variance Model Equations Below C

C {e.g. V(1) = (PV(1) + PV(2)*Y(1))**2 } C

C----c------C

V(1) = (PV(1) + PV(2)*Y(1))**2

C------C

Return

End

C######################################################################C

Subroutine COVMOD(Pmean, ICmean, PC)

C Defines any covariate model equations (MLEM, ITS)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Real*8 PC(MaxNCP)

Real*8 Pmean(MaxNSP+MaxNDE), ICmean(MaxNDE)

C------C

C Enter # of Covariate Parameters C

C----c------C

NCparam = 0 ! Enter # of Covariate Parameters.

C------C

C Enter Symbol for Covariate Params {eg: PCsym(1)='CLRenal'} C

C----c------C

C------C

C For the Model Params. that Depend on Covariates Enter the Equation C

C {e.g. Pmean(1) = PC(1)*R(2) } C

C----c------C

C------C

Return

End

C######################################################################C

Subroutine POPINIT(PmeanI,ICmeanI,PcovI,ICcovI, PCI)

C Initial parameter values for population program parameters (ITS, MLEM)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Integer I,J

Real*8 PmeanI(MaxNSP+MaxNDE), ICmeanI(MaxNDE)

Real*8 PcovI(MaxNSP+MaxNDE,MaxNSP+MaxNDE), ICcovI(MaxNDE,MaxNDE)

Real*8 PCI(MaxNCP)

C------C

C Enter Initial Values for Population Means C

C { e.g. PmeanI(1) = 10.0 } C

C----c------C

C------C

C Enter Initial Values for Pop. Covariance Matrix (Lower Triang.) C

C { e.g. PcovI(2,1) = 0.25 } C

C----c------C

C------C

C Enter Values for Covariate Model Parameters C

C { e.g. PCI(1) = 2.0 } C

C----c------C

C------C

Return

End

C######################################################################C

Subroutine PRIOR(Pmean,Pcov,ICmean,ICcov)

C Parameter mean and covariance values for MAP estimation (ID,NPD,STS)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Integer I,J

Real*8 Pmean(MaxNSP+MaxNDE), ICmean(MaxNDE)

Real*8 Pcov(MaxNSP+MaxNDE,MaxNSP+MaxNDE), ICcov(MaxNDE,MaxNDE)

C------C

C Enter Nonzero Elements of Prior Mean Vector C

C { e.g. Pmean(1) = 10.0 } C

C----c------C

C------C

C Enter Nonzero Elements of Covariance Matrix (Lower Triang.) C

C { e.g. Pcov(2,1) = 0.25 } C

C----c------C

C------C

Return

End

C######################################################################C

Subroutine SPARAM(PS,P,IC)

Implicit None

Include 'globals.inc'

Real*8 PS(MaxNSECP), P(MaxNSP+MaxNDE), IC(MaxNDE)

Real*8 Kp1,Kp2,V1,V2,Vp,BW,ECF

C------C

C Enter Equations Defining Secondary Paramters C

C { e.g. PS(1) = P(1)*P(2) } C

C----c------C

Kp1 = P(3)

Kp2 = P(4)

V1 = P(6)

CC----ECF is Extracelluar fluid------

ECF = 18.200

V2 = ECF-V1-Vp

CC----Cp is blood concentration---

Vp =5.200

PS(1) = Vp+Kp1*V1+Kp2*V2

C------C

Return

End

C######################################################################C

Subroutine AMAT(A)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Integer I,J

Real*8 A(MaxNDE,MaxNDE)

DO I=1,Ndeqs

Do J=1,Ndeqs

A(I,J)=0.0D0

End Do

C------C

C Enter non zero elements of state matrix {e.g. A(1,1) = -P(1) } C

C----c------C

C------C

Return

End

C######################################################################C

ADAPT-5 code for model in Figure-3

**********************************************************************

C ADAPT *

C Version 5 *

C**********************************************************************

C *

C MODEL *

C *

C This file contains Fortran subroutines into which the user *

C must enter the relevant model equations and constants. *

C Consult the User's Guide for details concerning the format for *

C entered equations and definition of symbols. *

C *

C 1. Symbol- Parameter symbols and model constants *

C 2. DiffEq- System differential equations *

C 3. Output- System output equations *

C 4. Varmod- Error variance model equations *

C 5. Covmod- Covariate model equations (ITS,MLEM) *

C 6. Popinit- Population parameter initial values (ITS,MLEM) *

C 7. Prior - Parameter mean and covariance values (ID,NPD,STS) *

C 8. Sparam- Secondary parameters *

C 9. Amat - System state matrix *

C *

C**********************************************************************

C######################################################################C

Subroutine SYMBOL

Implicit None

Include 'globals.inc'

Include 'model.inc'

C------C

C Enter as Indicated C

C----c------C

NDEqs = 9 ! Enter # of Diff. Eqs.

NSParam = 8 ! Enter # of System Parameters.

NVparam = 2 ! Enter # of Variance Parameters.

NSecPar = 1 ! Enter # of Secondary Parameters.

NSecOut = 0 ! Enter # of Secondary Outputs (not used).

Ieqsol = 1 ! Model type: 1 - DIFFEQ, 2 - AMAT, 3 - OUTPUT only.

Descr = 'minimal-PBPK with hepatic compartment'

C------C

C Enter Symbol for Each System Parameter (eg. Psym(1)='Kel') C

C----c------C

Psym(1)='f1'

Psym(2)='f2'

Psym(3)='Kp'

Psym(4)='CLint'

Psym(5)='V1'

Psym(6)='ka'

C-----—FG is pre-hepatic bioavailability------

Psym(7)='FG'

C-----—CLnh is non-hepatic clearance------

Psym(8)='CLnh'

C------C

C Enter Symbol for Each Variance Parameter {eg: PVsym(1)='Sigma'} C

C----c------C

PVsym(1)='intercept'

PVsym(2)='slope'

C------C

C Enter Symbol for Each Secondary Parameter {eg: PSsym(1)='CLt'} C

C----c------C

PSsym(1)='Vss'

C------C

Return

End

C######################################################################C

Subroutine DIFFEQ(T,X,XP)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Real*8 T,X(MaxNDE),XP(MaxNDE),Qco,Kp,f1,f2,V1,V2,Vp,CLint,f

Real*8 BW,ka,FG,Q,VL,CLnh

C------C

C Enter Differential Equations Below {e.g. XP(1) = -P(1)*X(1) } C

C----c------C

f1 = P(1)

f2 = P(2)

Kp = P(3)

CLint = P(4)

V1 = P(5)

ka = P(6)

FG = P(7)

CLnh = P(8)

CC----body weight-----

BW = 70

CC----Cp is blood concentration---

Vp = 5.200

V2 = BW-Vp-V1-VL

cc----Oco is cardiac output------

Qco = 5.600-Q

f = f1+f2

cc----Q is portal vein blood flow------

Q = 87/60

cc----VL is liver volume------

VL = 1.69

cc-----Oral------

CC---Drug Absorption compartment

XP(1) = -ka*X(1)

cc---Liver Compartment

XP(2) = ka*X(1)*FG + Q*X(3)-((X(2)/VL)/Kp)*Q

c -((X(2)/VL)/Kp)*CLint

c----blood compart-----

IF(f .gt. 1) then

XP(3) = 0

else

XP(3) = ((X(2)/VL)/Kp*Q+f1*Qco*X(4)/Kp + f2*Qco*X(5)/Kp -

c (f1*Qco+f2*Qco+Q+CLnh)*X(3))/Vp

endif

c----Compart1------

XP(4) = (f1*Qco*X(3) - f1*Qco* X(4)/Kp)/V1

c----Compart2-----

XP(5) = (f2*Qco*X(3) - f2*Qco* X(5)/Kp)/V2

ccc-----IV------

C----Liver compartment------

XP(6) = Q*X(7)/Vp - ((X(6)/VL)/Kp)*Q-((X(6)/VL)/Kp)*CLint

c----blood compart-----

IF(f .gt. 1) then

XP(7) = 0

else

XP(7) = R(1)+ f1*Qco*X(8)/Kp + f2*Qco*X(9)/Kp+((X(6)/VL)/Kp)

c *Q-(f1*Qco+f2*Qco+Q+CLnh)*X(7)/Vp

endif

c----tissue Compartment 1------

XP(8) = (f1*Qco*X(7)/Vp - f1*Qco* X(8)/Kp)/V1

c----tissue Compartment 2-----

XP(9) = (f2*Qco*X(7)/Vp - f2*Qco* X(9)/Kp)/V2

C------C

Return

End

C######################################################################C

Subroutine OUTPUT(Y,T,X)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Real*8 Y(MaxNOE),T,X(MaxNDE),Vp

C------C

C Enter Output Equations Below {e.g. Y(1) = X(1)/P(2) } C

C----c------C

Vp = 5.2

Y(1) = X(3)

Y(2) = X(7)/Vp

C------C

Return

End

C######################################################################C

Subroutine VARMOD(V,T,X,Y)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Real*8 V(MaxNOE),T,X(MaxNDE),Y(MaxNOE)

C------C

C Enter Variance Model Equations Below C

C {e.g. V(1) = (PV(1) + PV(2)*Y(1))**2 } C

C----c------C

V(1) = (PV(1) + PV(2)*Y(1))**2

V(2) = (PV(1) + PV(2)*Y(2))**2

C------C

Return

End

C######################################################################C

Subroutine COVMOD(Pmean, ICmean, PC)

C Defines any covariate model equations (MLEM, ITS)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Real*8 PC(MaxNCP)

Real*8 Pmean(MaxNSP+MaxNDE), ICmean(MaxNDE)

C------C

C Enter # of Covariate Parameters C

C----c------C

NCparam = 0 ! Enter # of Covariate Parameters.

C------C

C Enter Symbol for Covariate Params {eg: PCsym(1)='CLRenal'} C

C----c------C

C------C

C For the Model Params. that Depend on Covariates Enter the Equation C

C {e.g. Pmean(1) = PC(1)*R(2) } C

C----c------C

C------C

Return

End

C######################################################################C

Subroutine POPINIT(PmeanI,ICmeanI,PcovI,ICcovI, PCI)

C Initial parameter values for population program parameters (ITS, MLEM)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Integer I,J

Real*8 PmeanI(MaxNSP+MaxNDE), ICmeanI(MaxNDE)

Real*8 PcovI(MaxNSP+MaxNDE,MaxNSP+MaxNDE), ICcovI(MaxNDE,MaxNDE)

Real*8 PCI(MaxNCP)

C------C

C Enter Initial Values for Population Means C

C { e.g. PmeanI(1) = 10.0 } C

C----c------C

C------C

C Enter Initial Values for Pop. Covariance Matrix (Lower Triang.) C

C { e.g. PcovI(2,1) = 0.25 } C

C----c------C

C------C

C Enter Values for Covariate Model Parameters C

C { e.g. PCI(1) = 2.0 } C

C----c------C

C------C

Return

End

C######################################################################C

Subroutine PRIOR(Pmean,Pcov,ICmean,ICcov)

C Parameter mean and covariance values for MAP estimation (ID,NPD,STS)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Integer I,J

Real*8 Pmean(MaxNSP+MaxNDE), ICmean(MaxNDE)

Real*8 Pcov(MaxNSP+MaxNDE,MaxNSP+MaxNDE), ICcov(MaxNDE,MaxNDE)

C------C

C Enter Nonzero Elements of Prior Mean Vector C

C { e.g. Pmean(1) = 10.0 } C

C----c------C

C------C

C Enter Nonzero Elements of Covariance Matrix (Lower Triang.) C

C { e.g. Pcov(2,1) = 0.25 } C

C----c------C

C------C

Return

End

C######################################################################C

Subroutine SPARAM(PS,P,IC)

Implicit None

Include 'globals.inc'

Real*8 PS(MaxNSECP), P(MaxNSP+MaxNDE), IC(MaxNDE)

Real*8 Qco,Kp,V1,V2,Vp,BW,CLint

C------C

C Enter Equations Defining Secondary Paramters C

C { e.g. PS(1) = P(1)*P(2) } C

C----c------C

Kp = P(3)

CLint = P(4)

V1 = P(5)

BW = 70

V2 = BW-V1-Vp-1.69

Vp = 5.2

PS(1) = Vp+Kp*V1+Kp*V2

C------C

Return

End

C######################################################################C

Subroutine AMAT(A)

Implicit None

Include 'globals.inc'

Include 'model.inc'

Integer I,J

Real*8 A(MaxNDE,MaxNDE)

DO I=1,Ndeqs

Do J=1,Ndeqs

A(I,J)=0.0D0

End Do

C------C

C Enter non zero elements of state matrix {e.g. A(1,1) = -P(1) } C

C----c------C

C------C

Return

End

C######################################################################C