Pharmacokinetics and Pharmacodynamics of GS-9350: A Novel Pharmacokinetic Enhancer Without Anti-HIV Activity

被引：180

作者：

Mathias, A. A. ^{[1
]}

German, P. ^{[1
]}

Murray, B. P. ^{[1
]}

Wei, L. ^{[1
]}

Jain, A. ^{[1
]}

West, S. ^{[1
]}

Warren, D. ^{[1
]}

Hui, J. ^{[1
]}

Kearney, B. P. ^{[1
]}

机构：

[1] Gilead Sci Inc, Foster City, CA 94404 USA

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2010年 / 87卷 / 03期

关键词：

BOOSTED PROTEASE INHIBITORS; CYTOCHROME-P450 3A ACTIVITY; INFECTED PATIENTS; POPULATION PHARMACOKINETICS; HIV-1-INFECTED PATIENTS; P-GLYCOPROTEIN; CYP3A ACTIVITY; HEPATIC CYP3A; RITONAVIR; MIDAZOLAM;

D O I：

10.1038/clpt.2009.228

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

GS-9350 is a new chemical entity under development as a potent, mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) isoforms. Its intended use is to increase the systemic exposure of coadministered agents that are metabolized by CYP3A enzymes. Unlike ritonavir, which is in current clinical use for this purpose, GS-9350 is devoid of anti-HIV activity. The pharmacokinetics of GS-9350 and its efficacy in increasing systemic exposure of the probe CYP3A substrate midazolam were examined in a study involving single- and multiple-dose escalations of GS-9350 from 50 to 400 mg. Single-dose escalation from 50 to 400 mg resulted in a 164-fold increase in GS-9350 exposure, whereas multiple-dose escalation in the dosage range of 50-300 mg resulted in a 47-fold increase in exposure. GS-9350 potently inhibited midazolam apparent clearance (95% reduction), similar in effect to ritonavir 100 mg. GS-9350 was generally well tolerated at all doses, and there was no evidence of dose-limiting toxicity. Establishing proof-of-concept, GS-9350 is currently under phase II development as a potential alternative to ritonavir for use with antiretroviral agents (including the HIV integrase inhibitor elvitegravir) that are often prescribed along with a "booster" drug.

引用

页码：322 / 329

页数：8

共 30 条

[1] The Effect of Atazanavir and Atazanavir/Ritonavir on UDP-Glucuronosyltransferase Using Lamotrigine as a Phenotypic Probe [J].