Re: Prednisone and Prednisolone PPK
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
Alice Nichols.vcf
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