NONMEM Users Network Archive

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Re: higher AUC after bolus compared to infusion?

From: MALAZ ABUTARIF <mabutarif>
Date: Thu, 4 Dec 2008 09:29:25 -0500

Dear,
This can most likely be described by a model of non-instantaneous and
potentially irreversible binding kinetics to the intracellular
proteins/structures.
With bolus, you see the drug in plasma (hence higher AUC) before it binds t=
o
the internal proteins irreversably.
With infusions, more of the drug has time to bind irreversably to the
internal structures, which is a tissue clearance (higher apparent clearance
with infusions leading to lower AUC).
At higher doses, you may saturate the proteins/internal structures and you
no longer have that tissue clearance. And after a certain dose level, you
will likely see more linear kinetics.

I've done some research on that some time ago (modeled the non-instantaneou=
s
kinetics and measured them experimentally, then simulated a clinical profil=
e
where these non-instantaneous kinetics of protein binding played a role in
the kinetics of the drug), a small part of the work was published but the
remainder has not been published yet (I'm about 7 years late on writing tha=
t
paper).

Malaz A AbuTarif, Ph.D., M.B.A.
Schering-Plough
Kenilworth, NJ


On 12/4/08, nele.plock
wrote:
>
> Dear all,
>
> I have trouble modeling some rat PK data obtained after intravenous
> dosing. I have dense data for two different doses, given either as bolus,
> half-hour or 3-hour infusion. We know that the compound has a large
> binding affinity to intracellular structures and therefore has a high
> volume of distribution (~100L/kg in rats). However, what we observed in
> the mentioned study is that the AUC after bolus dosing is ~3 times higher
> than after infusions (no difference between 0.5 and 3 h), and this was
> observed for both dose groups (effect a bit less pronounced for high dose=
,
> but still there). Noncompartmental analysis indicates that this is due to
> lower clearance and not a change in Vss. At the moment I have no idea wha=
t
> kind of model would capture an observation like this. Has anybody ever
> observed something like this, and even better, have some ideas on model
> coding? Any ideas would be welcome!
>
> Best regards
> Nele
> _________________________________________
>
> Bayer Schering Pharma AG
> Development Pharmacokinetics
> Berlin, S109, 03, 306A
> Phone: +49 30 468-15146
> Fax: +49 30 468-11527
> E-mail: nele.plock
> Web: http://www.bayerscheringpharma.de
>
> Vorstand: Andreas Fibig, Vorsitzender | Werner Baumann, Andreas Busch,
> Ulrich Köstlin, Kemal Malik, Bernd Metzner, Gunnar Riemann
> Vorsitzender des Aufsichtsrats: Werner Wenning
> Sitz der Gesellschaft: Berlin | Eintragung: Amtsgericht Charlottenburg HR=
B
> 283 B
>
>

Received on Thu Dec 04 2008 - 09:29:25 EST

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