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Re: Prednisone and Prednisolone PPK

From: Jian Xu <alanub>
Date: Fri, 5 Dec 2008 07:01:03 -0800 (PST)

Hi, Chandra, 1: You may need to use free steroid concentrations to mod=
el. (in vitro protein binding information is available in Dr. Jusko's paper=
s (early 90s')) 2: You will have identifiability problem for your model=
 if only prednisolone or prednione is given (even you measured both ste=
roid concentrations.) You can fix a few parameters in order to get yo=
ur model stable. We published a paper last year for prednisolone and predni=
sone PK/PD (not POP approach), and you may get some information from it. (h=
ttp://www.ncbi.nlm.nih.gov/pubmed/17318442) Good luck, Jian =

wyeth.com> To: nmusers
7:57:16 PM Subject: Re: [NMusers] Prednisone and Prednisolone PPK =

 PPK in humans given a PO dose of prednisone. Note that prednisone is c=
onverted to prednisolone during the first-pass and prednisolone is conver=
ted 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 n=
ot appear to be stable and sensitive to initial estimates . Is there an=
 issue of "identifiability" in this model? does anyone has already worked o=
n PPK of this drug? Furthermore, I would like to model the inhibition of co=
nversion of prednisone to prednisolone as function of time and test drug co=
ncentration. Any leads much appreciated. Regards, - Chandra =


SUBROUTINES ADVAN8 TRANS1 TOL=5 $MODEL NPAR=7 NCOMP=3    COMP=
=(DEPOT,DEFDOSE)    COMP=(PARENT)    COMP=(METAB) $P=
K  KA=THETA(1)*EXP(ETA(1))  VP=THETA(2)*EXP(ETA(2))  =
   CLP=THETA(3)*EXP(ETA(3))  VMT=THETA(4)*EXP(ETA(4))  K=
F=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=IP=
RED+ERR(2)   Y=R1*Y2+R2*Y3   IRES=EXP(DV)-EXP(IPRED) $THET=
A ....... $OMEGA ....... $SIGMA ....... $EST SIG=5 METHOD=
=1 PRINT=1 MAX=9999 POSTHOC NOABORT
Received on Fri Dec 05 2008 - 10:01:03 EST

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