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RE: Question about modeling variable absorption kinetics

From: Lavigne, Jean <jean.lavigne>
Date: Fri, 20 Jul 2012 14:35:17 +0000

Dear Claire,

You may want to look at Zhou's paper, it has a summary of the different typ=
e of absorption models.

Best regards,

Jean

Reference:

Pharmacokinetic Strategies in Deciphering Atypical Drug Absorption Profiles=
. Honghui Zhou, J Clin Pharmacol 2003;43:211-227



From: owner-nmusers
 Behalf Of Xu, Claire
Sent: Friday, July 20, 2012 12:05 AM
To: nmusers
Subject: [NMusers] Question about modeling variable absorption kinetics

Hi NMusers,

I am trying to develop a population model of a drug that was given at a sin=
gle dose using the PK data from two studies with different dosage. In one s=
tudy with the higher dose (n=26, four-way cross-over), it seems to have t=
hree different patterns of kinetics: 1. the first measured concentration is=
 Cmax (fast absorption); 2. a secondary peak; 3. more common oral PK with 1=
st-order Ka(normal absorption). In the other study with lower dose (n=46,=
 two-way cross-over), the overall kinetics are less variable within the stu=
dy. But there are about 30% subjects have about 50% higher Cmax than other=
s.

I tried one-compartment, two-compartment and ALAG models to fit the PK from=
 the first study with higher dose and also played with the introduction of =
BOV and BSV on Ka and/or TLAG. All the models generally cannot capture the =
absorption very well with an underprediction of Cmax. And None of the compl=
ex models really gave improved fitting compared to simple one-compartment m=
odel. I also tested transit model and it didn't improve the fitting either.

Then, I focused on the PK with fast and normal absorption only and exclude =
the PK with the secondary peak. I found that two-compartment model can give=
 good fitting for PK with fast absorption and normal absorption,respectivel=
y. The estimated Ka for fast and normal absorption PK are three times diffe=
rent, and then I tried mixture model on Ka to fit the two PK dataset togeth=
er. But it suffered boundary failure and the percentage of the subpopulatio=
ns can not be estimated.

For the second study with lower dose, I have similar problem. The majority =
of Cmax is underpredicted, but I have good fitting of elimination phase in =
both case.

It seems that I exhausted the possibilities that I can think of. Can anyone=
 give some comments or suggestions ?

Thanks a lot!

Best,
--
Xu, Claire
Ph.D Candidate
Division of Clinical Pharmacology, Wishard Hospital
Indiana University School of Medicine
1001 West 10th Street, Myers W7122
Indianapolis, IN 46202
T - 317/7558242<tel:317%2F7558242>


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Received on Fri Jul 20 2012 - 10:35:17 EDT

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