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RE: Prednisone and Prednisolone PPK

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

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