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Re: higher AUC after bolus compared to infusion?

From: jeffrey.a.wald
Date: Thu, 4 Dec 2008 13:59:03 -0500

Volume and AUC are independent - AUC is defined by dose and clearance. You =

have stated that your estimate of Vss is not impacted so your experimental =

design is probably capturing enough of the PK profile to describe the
underlying phenomenon.

I think the best starting point is a michaelis-menten model with
diminished clearance at high plasma concentrations.

Regards, Jeff
Jeff Wald, PhD
jeffrey.a.wald 'at'
Director, Clinical Pharmacology Modeling and Simulation
P Please consider the ENVIRONMENT before printing this mail P

Sent by: owner-nmusers
04-Dec-2008 04:02

[NMusers] higher AUC after bolus compared to infusion?

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 what =

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

Bayer Schering Pharma AG
Development Pharmacokinetics
Berlin, S109, 03, 306A
Phone: +49 30 468-15146
Fax: +49 30 468-11527
E-mail: nele.plock

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 HRB =

283 B

Received on Thu Dec 04 2008 - 13:59:03 EST

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