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Re: Prednisone and Prednisolone PPK

From: Chandrasekhar Udata <Udatac>
Date: Thu, 04 Dec 2008 19:57:16 -0500

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 "identifia=
bility" 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

Received on Thu Dec 04 2008 - 19:57:16 EST

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