NONMEM Users Network Archive

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Re: Subpopulation

From: jeffrey.a.wald
Date: Tue, 12 Aug 2008 14:46:36 -0400

Huali - If the goal of making a very arbitrary decision as to which
patient exhibits linear versus nonlinear PK is to "get a better look" then
that is fine. It may reveal an underlying relationship in the data. So
for example, you may wish to plot the resulting post-hoc values of
clearances and volumes versus dose to understand what sort of nonlinearity
is present. Does the apparent nonlinearity produce higher or lower than
expected exposures? Is it a clearance or absorption issue? however, the
danger in such an approach is that you are making very subjective
decisions as to what is and is not nonlinear.

With the limited info you have provided I can only make general
assertions. However, such an exercise should only be used as an
intermediate, exploratory tool to understand what is truly occurring with
this drug which will then permit building a more optimal model that
encompasses all the data. If the drug is subject to polymorphic
metabolism, or some precipitant of a drug interaction is present then one
might consider patients as subpopulations using either known values of
covariates or a mixture model. However, more likely is that there is some
underlying continuous distribution of Km in your population and that some
fraction of your high dose patients have a low enough Km and have achieved
high enough concentrations so as to exhibit an obviously nonlinear
profile. A similar distribution of bioavailability might explain data
moving in the opposite direction.

With data as rich as you have described in your posting, it seems like you
should have a very good chance of identifying the underlying properties
that have produced your observations.



"Huali Wu" <hualiw
Sent by: owner-nmusers
12-Aug-2008 12:14

[NMusers] Subpopulation

Dear NMusers:
I am trying to fit a dataset with 13 dose levels. The highest dose is
about 10 times of the lowest dose. Each patient receive one dose and were
sampled intensively up to 7 days. The results of individual PK analysis
shown linear kinetics for some of the patients and nonlinear kinetics for
the other patients. I have tried to fit all of them together. But my
advisor wants me to fit linear patients and nonlinear patients separately
to get a better look of fitting.
Additionally, all the nonlinear patients are from higher dose levels. But
not all the patients in higher dose levels shown nonlinear kinetics. So my
question is which way is more appropriate in this case? Should I fit them
all together or separately? Could these two types of patients be
considered as subpopulations?
Any comment or suggestion will be highly appreciated.
Best regards,

Received on Tue Aug 12 2008 - 14:46:36 EDT

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