Re: higher AUC after bolus compared to infusion?
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 to
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-instantaneous
kinetics and measured them experimentally, then simulated a clinical profile
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 that
paper).
Malaz A AbuTarif, Ph.D., M.B.A.
Schering-Plough
Kenilworth, NJ
Quoted reply history
On 12/4/08, [EMAIL PROTECTED] <[EMAIL PROTECTED]>
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 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
> Nele
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