From: Fatemeh Akhlaghi, PhD <*fak4939u*>

Date: Thu, 4 Dec 2008 21:21:50 -0500

Chandra,

You must remember that prednisolone is bound in a saturable manner to plasma

proteins resulting in the non-linear PK. Prednisone plasma protein binding

however is not satuable. Modeling the unbound prednisolone data or estimating

unbound conc from total conc and binding proteins (CBG and albumin) may

therefore help the model.

Also there is identifiability problem with the prednisolone to prednisone

conversion. Dr. Jusko has successfully modeled this conversion in animal

models but the animals were given the drug either as prednisolone or

prednisone.

Hope it helps.

Fatemeh Akhlaghi

*>===== Original Message From "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 "identifiability" 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
*

Fatemeh Akhlaghi, PharmD, PhD

Associate Professor in Pharmacokinetics

Biomedical and Pharmaceutical Sciences (BPS)

University of Rhode Island

125 Fogarty Hall, 41 Lower College Road

Kingston, RI 02881, USA

Phone/Fax: (401) 874 9205/(401) 874 2181

Email: fatemeh

Laboratory Website: http://www.uri.edu/pharmacy/faculty/aps/akhlaghi

Received on Thu Dec 04 2008 - 21:21:50 EST

Date: Thu, 4 Dec 2008 21:21:50 -0500

Chandra,

You must remember that prednisolone is bound in a saturable manner to plasma

proteins resulting in the non-linear PK. Prednisone plasma protein binding

however is not satuable. Modeling the unbound prednisolone data or estimating

unbound conc from total conc and binding proteins (CBG and albumin) may

therefore help the model.

Also there is identifiability problem with the prednisolone to prednisone

conversion. Dr. Jusko has successfully modeled this conversion in animal

models but the animals were given the drug either as prednisolone or

prednisone.

Hope it helps.

Fatemeh Akhlaghi

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 "identifiability" 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.

Fatemeh Akhlaghi, PharmD, PhD

Associate Professor in Pharmacokinetics

Biomedical and Pharmaceutical Sciences (BPS)

University of Rhode Island

125 Fogarty Hall, 41 Lower College Road

Kingston, RI 02881, USA

Phone/Fax: (401) 874 9205/(401) 874 2181

Email: fatemeh

Laboratory Website: http://www.uri.edu/pharmacy/faculty/aps/akhlaghi

Received on Thu Dec 04 2008 - 21:21:50 EST