Population pharmacokinetic model for a novel oral hypoglycemic formed in vivo: comparing the use of active metabolite data alone versus using data of upstream and downstream metabolites.

Abstract:

:The purpose of this analysis was to develop a population pharmacokinetic model for CS-917, an oral hypoglycemic prodrug, and its 3 metabolites. The population pharmacokinetic model was used to predict exposure of the active moiety R-125338 and thus to identify potential CS-917 dosage reduction criteria. The dataset included 6 phase I and IIa studies in patients with type 2 diabetes mellitus. The pharmacokinetic profile of CS-917 and its metabolites was described by a series of linked 1- and 2-compartmental models. Simulations showed that moderate renal impairment has a clinically significant impact on exposure to R-125338. A separate population pharmacokinetic analysis of R-125338 alone revealed similar results. In conclusion, a population pharmacokinetic model fit to the active moiety alone yielded similar predictions and substantially reduced the analysis time compared to the more complex model developed for CS-917 and its metabolites. Increased exposure to R-125338 in the presence of moderate renal impairment may be an important consideration for dose selection.

journal_name

J Clin Pharmacol

authors

Kastrissios H,Walker JR,Carrothers TJ,Kshirsagar S,Khariton T,Habtemariam B,Mager DE,Rohatagi S

doi

10.1177/0091270010396373

subject

Has Abstract

pub_date

2012-03-01 00:00:00

pages

404-15

issue

3

eissn

0091-2700

issn

1552-4604

pii

0091270010396373

journal_volume

52

pub_type

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