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Re: Simultaneous vs sequential for modeling parent AND metabolites in pop PK

From: andreas lindauer <lindauer>
Date: Thu, 11 Dec 2008 11:16:31 +0100

Nick, James and all,

 

I would like to add to the present discussion that when one estimates =
CL/fm
or V/fm of the metabolite, one should be aware that if the parent drug =
is
given orally (bioavailability unknown) this also affects the metabolite
parameters. In this case only CL/(fm*F) and V/(fm*F) can be estimated. =
As
has been already stated, this is not a problem for a descriptive model.
However, especially for simulations it is important to account for the
correlation of these parameters because CL/F and V/F of the parent as =
well
as CL/(fm*F) and V/(fm*F) of the metabolite are all correlated because =
of F
and fm. Thus my questions to the group: are the between subject
variabilities of fm and F identifiable? I know that one can estimate =
them by
fixing F and fm to 1 and estimate their omegas, but will they really be
identifiable and give meaningful results? I'm wondering because also the
parent drug's clearance and the fraction metabolised are related. =
Shouldn't
this also be taken into account?

Things get even more complicated when a significant first-past effect
occurs. Then (assuming 100% absorption) the remainder of the unknown F, =
i.e.
the fraction of the parent drug that is converted to the metabolite via
first-pass (1-F) must now also be considered for the metabolite =
parameters
and one estimates CL/(fm*F*(1-F)) and V/(fm*F*(1-F)). Or is F (assuming
complete absorption) identifiable in this case?

I'm looking forward to your comments.

Regards, Andreas.

 

____________________________

 

Andreas Lindauer

 

Department of Clinical Pharmacy

Institute of Pharmacy

University of Bonn

An der Immenburg 4

D-53121 Bonn

 

phone: + 49 228 73 5781

fax: + 49 228 73 9757

 


Received on Thu Dec 11 2008 - 05:16:31 EST

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