From: Alice Nichols <*NICHOLA2*>

Date: Fri, 05 Dec 2008 10:50:20 -0500

setting a nonlinear CL from prednisone to prednisolone is probably a =

reasonable fix, a hill equation instead of just estimating a Cl could =

work, although you'd probably need to fix one of the terms in the hill =

equation since data is limited

Alice.

Alice I Nichols, PhD

Sr Director

Early Development and Clinical Pharmacology

Wyeth Research

500 Arcola Rd

Collegeville, PA 19426

tel: 484-865-8741/ fax: 484-865-9075

nichola2

*>>> "Chandrasekhar Udata" <Udatac *

Dear all,

I am working on modelling prednisone and prednisolone PPK in humans given =

a PO dose of prednisone. Note that prednisone is converted to prednisolone =

during the first-pass and prednisolone is converted back to prednisone =

(reversible metabolism). I used a simple 2-cmt PK model (see the code =

below) that seems to work. However, the model does not appear to be =

stable and sensitive to initial estimates . Is there an issue of "identifia=

bility" in this model? does anyone has already worked on PPK of this drug? =

Furthermore, I would like to model the inhibition of conversion of =

prednisone to prednisolone as function of time and test drug concentration.=

Any leads much appreciated.

Regards,

- Chandra

----------------------------------------------------------------------

$INPUT C ID TIME DV AMT CMT EVID MDV

$DATA pred2.CSV IGNORE=C

$SUBROUTINES ADVAN8 TRANS1 TOL=5

$MODEL NPAR=7 NCOMP=3

COMP=(DEPOT,DEFDOSE)

COMP=(PARENT)

COMP=(METAB)

$PK

KA=THETA(1)*EXP(ETA(1))

VP=THETA(2)*EXP(ETA(2))

CLP=THETA(3)*EXP(ETA(3))

VMT=THETA(4)*EXP(ETA(4))

KF=THETA(5)*EXP(ETA(5))

KB=THETA(6)*EXP(ETA(6))

CLM=THETA(7)*EXP(ETA(7))

S2=VP

S3=VMT

$DES

DADT(1)=-KA*A(1)

DADT(2)=KA*A(1)-KF*A(2)+KB*A(3)-CLP*A(2)/VP

DADT(3)=KF*A(2)-KB*A(3)-CLM*A(3)/VMT

$ERROR

FLAG=0

IF(AMT.NE.0) FLAG=1

IPRED=LOG(F+FLAG)

R1=0

IF (CMT.EQ.2) R1=1

R2=0

IF (CMT.EQ.3) R2=1

Y2=IPRED+ERR(1)

Y3=IPRED+ERR(2)

Y=R1*Y2+R2*Y3

IRES=EXP(DV)-EXP(IPRED)

$THETA .......

$OMEGA .......

$SIGMA .......

$EST SIG=5 METHOD=1 PRINT=1 MAX=9999 POSTHOC NOABORT

Received on Fri Dec 05 2008 - 10:50:20 EST

Date: Fri, 05 Dec 2008 10:50:20 -0500

setting a nonlinear CL from prednisone to prednisolone is probably a =

reasonable fix, a hill equation instead of just estimating a Cl could =

work, although you'd probably need to fix one of the terms in the hill =

equation since data is limited

Alice.

Alice I Nichols, PhD

Sr Director

Early Development and Clinical Pharmacology

Wyeth Research

500 Arcola Rd

Collegeville, PA 19426

tel: 484-865-8741/ fax: 484-865-9075

nichola2

Dear all,

I am working on modelling prednisone and prednisolone PPK in humans given =

a PO dose of prednisone. Note that prednisone is converted to prednisolone =

during the first-pass and prednisolone is converted back to prednisone =

(reversible metabolism). I used a simple 2-cmt PK model (see the code =

below) that seems to work. However, the model does not appear to be =

stable and sensitive to initial estimates . Is there an issue of "identifia=

bility" in this model? does anyone has already worked on PPK of this drug? =

Furthermore, I would like to model the inhibition of conversion of =

prednisone to prednisolone as function of time and test drug concentration.=

Any leads much appreciated.

Regards,

- Chandra

----------------------------------------------------------------------

$INPUT C ID TIME DV AMT CMT EVID MDV

$DATA pred2.CSV IGNORE=C

$SUBROUTINES ADVAN8 TRANS1 TOL=5

$MODEL NPAR=7 NCOMP=3

COMP=(DEPOT,DEFDOSE)

COMP=(PARENT)

COMP=(METAB)

$PK

KA=THETA(1)*EXP(ETA(1))

VP=THETA(2)*EXP(ETA(2))

CLP=THETA(3)*EXP(ETA(3))

VMT=THETA(4)*EXP(ETA(4))

KF=THETA(5)*EXP(ETA(5))

KB=THETA(6)*EXP(ETA(6))

CLM=THETA(7)*EXP(ETA(7))

S2=VP

S3=VMT

$DES

DADT(1)=-KA*A(1)

DADT(2)=KA*A(1)-KF*A(2)+KB*A(3)-CLP*A(2)/VP

DADT(3)=KF*A(2)-KB*A(3)-CLM*A(3)/VMT

$ERROR

FLAG=0

IF(AMT.NE.0) FLAG=1

IPRED=LOG(F+FLAG)

R1=0

IF (CMT.EQ.2) R1=1

R2=0

IF (CMT.EQ.3) R2=1

Y2=IPRED+ERR(1)

Y3=IPRED+ERR(2)

Y=R1*Y2+R2*Y3

IRES=EXP(DV)-EXP(IPRED)

$THETA .......

$OMEGA .......

$SIGMA .......

$EST SIG=5 METHOD=1 PRINT=1 MAX=9999 POSTHOC NOABORT

- application/octet-stream attachment: Alice_Nichols.vcf