Hi, Chandra, 1: You may need to use free steroid concentrations to model. (in vitro protein binding information is available in Dr. Jusko's papers (early 90s')) 2: You will have identifiability problem for your model if only prednisolone or prednione is given (even you measured both steroid concentrations.)
You can fix a few parameters in order to get your model stable. We published a paper last year for prednisolone and prednisone PK/PD (not POP approach), and you may get some information from it. (http://www.ncbi.nlm.nih.gov/pubmed/17318442) Good luck, Jian ________________________________ From: Chandrasekhar Udata <[EMAIL PROTECTED]> To: nmusers@globomaxnm.com Sent: Thursday, December 4, 2008 7:57:16 PM Subject: Re: [NMusers] Prednisone and Prednisolone PPK 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
