title: 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.
authors.affiliation: Pharsight Corporation, Mountain View, California, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Kastrissios
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Walker
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Carrothers
authors.forename: Smita
authors.initials: S
authors.lastname: Kshirsagar
authors.forename: Tatiana
authors.initials: T
authors.lastname: Khariton
authors.forename: Bahru
authors.initials: B
authors.lastname: Habtemariam
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
authors.forename: Shashank
authors.initials: S
authors.lastname: Rohatagi
mesh_terms: D000368:Aged; D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D011355:Prodrugs; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*
chemical_list: D007004:Hypoglycemic Agents; D063065:Organophosphonates; D011355:Prodrugs; C574022:R-125338; D013844:Thiazoles; C502805:N,N'-((5-(2-amino-5-(2-methylpropyl)-4-thiazolyl)-2-furanyl)phosphinylidene)bis(alanine) diethyl ester; D000409:Alanine