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Question about modeling variable absorption kinetics

From: Xu, Claire <smartxucong>
Date: Fri, 20 Jul 2012 00:05:25 -0400

Hi NMusers,

I am trying to develop a population model of a drug that was given at a
single dose using the PK data from two studies with different dosage. In
one study with the higher dose (n=26, four-way cross-over), it seems to
have three different patterns of kinetics: 1. the first measured
concentration is Cmax (fast absorption); 2. a secondary peak; 3. more
common oral PK with 1st-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 study. But there are about 30% subjects have about 50%
higher Cmax than others.

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
complex models really gave improved fitting compared to simple
one-compartment model. 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,respectively. The estimated Ka for fast and normal absorption PK
are three times different, and then I tried mixture model on Ka to fit the
two PK dataset together. But it suffered boundary failure and the
percentage of the subpopulations 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!

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

Received on Fri Jul 20 2012 - 00:05:25 EDT

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