Compartmental absorption modeling and site of absorption studies to determine feasibility of an extended-release formulation of an HIV-1 attachment inhibitor phosphate ester prodrug

被引：46
作者：
Brown, Jonathan [1 ]
Chien, Caly [2 ]
Timmins, Peter [1 ]
Dennis, Andrew [1 ]
Doll, Walter [3 ]
Sandefer, Erik [3 ]
Page, Richard [3 ]
Nettles, Richard E. [2 ]
Zhu, Li [2 ]
Grasela, Dennis [2 ]
机构：
[1] Bristol Myers Squibb, Drug Prod Sci & Technol, Moreton CH46 1QW, Merseyside, England
[2] Bristol Myers Squibb, Discovery Med & Clin Pharmacol, Pennington, NJ 08534 USA
[3] Scintipharma Inc, Lexington, KY 40503 USA
来源：
JOURNAL OF PHARMACEUTICAL SCIENCES | 2013年 / 102卷 / 06期
关键词：
dissolution; colonic drug delivery; site-specific absorption; in silico modeling; prodrugs; CLINICAL PHARMACOKINETICS; AMPRENAVIR; DESIGN; DRUGS;
D O I：
10.1002/jps.23476
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
BMS-663068 is a phosphonooxymethyl ester prodrug under development for the treatment of HIV/AIDS. The prodrug is designed to overcome the solubility-limited bioavailability of the active moiety, BMS-626529. BMS-663068 is not absorbed from the gastrointestinal (GI) tract and requires enzymatic conversion by alkaline phosphatase to BMS-626529 immediately before absorption. In the light of the known short in vivo half-life of BMS-626529, compartmental absorption modeling was used to predict the potential feasibility of extended-release (ER) delivery to achieve target Cmax:Cmin ratios. To further refine the model with respect to colonic absorption, the regional absorption of BMS-626529 following delivery of BMS-663068 to upper and lower GI sites was characterized through a site of absorption study in human subjects. A refined model was subsequently applied to guide the development of ER tablet formulations. Comparisons of results from the refined model to the in vivo human pharmacokinetic data for three selected ER formulations demonstrate the utility of the model in predicting feasibility of ER delivery and in directing formulation development. (c) 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:17421751, 2013
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页码：1742 / 1751
页数：10
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