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 [EMAIL PROTECTED]
>>> "Chandrasekhar Udata" <[EMAIL PROTECTED]> 12/4/2008 7:57:16 PM >>> 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
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