NONMEM Users Network Archive

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Re: modelling strategy question

From: Nick Holford <n.holford>
Date: Mon, 10 Dec 2012 09:31:33 +1300

Emily,

Standard PK theory for linear models proposes that the distribution and
elimination processes are independent of input. It is well recognized
that if the input is slow (e.g. after SC dosing) that it may be
difficult to discern a fast distribution phase so that a one compartment
distribution model will fit the data as well as a two compartment model.
The rejection of a two compartment model on statistical grounds should
be seen as a limitation imposed by the data and not invalidation of
standard PK theory.

I suggest you fit the data simultaneously using a two compartment
distribution model e.g. using ADVAN4. This will allow you to use a
first-order input of the SC dose into a depot compartment (CMT=1) and a
direct input of the IV dose.into the central compartment (CMT=2) . The
SC input will distribute into a 2 compartment system as determined by
the IV data. You will need to use the CMT data item to signal to NONMEM
which compartment the AMT is to be put into depending on the route of
administration.

Best wishes,

Nick

On 10/12/2012 6:50 a.m., Emily Peters wrote:
>
>
> Hi all,
>
> I have the following issue. Maybe someone has a helpful hint?
>
> Data of a human cross over study (dense sampling) on the absolute
> bioavailability are to be modeled using NONMEM. In one period the drug
> is administered i.v., in the other s.c.
> It turns out that after the s.c. administration the kinetics follwo a
> 1-cmt model, while after the i.v. administration a 2-cmt model is
> observable (in each case quite clearly).
>
> Can anybody recommend how to fit that situation simulatneously?
>
> Thanks in advance,
>
> Emily

--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
tel:+64(9)923-6730 fax:+64(9)373-7090 mobile:+64(21)46 23 53
email: n.holford
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford

Received on Sun Dec 09 2012 - 15:31:33 EST

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