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
