Pharmacokinetics and Bioavailability of an Integrase and... : JAIDS Journal of Acquired Immune Deficiency Syndromes (original) (raw)

Clinical Science

Pharmacokinetics and Bioavailability of an Integrase and Novel Pharmacoenhancer-Containing Single-Tablet Fixed-Dose Combination Regimen for the Treatment of HIV

German, Polina PharmD; Warren, David MD; West, Steve BS; Hui, James PhD; Kearney, Brian P PharmD

From the Gilead Sciences, Inc, Foster City, CA.

Received for publication February 14, 2010; accepted May 10, 2010.

Parts of these data were presented at 16th Conference on Retroviruses and Opportunistic Infections; February 8-12, 2009; Montreal, Canada. Abstract number 40 plus oral presentation.

The authors are employees of Gilead Sciences, Inc. Gilead Sciences employees potentially own stock and/or hold stock options in the company.

Correspondence to: Polina German, PharmD, Gilead Sciences, Inc, 333 Lakeside Drive, Foster City, CA 94404 (e-mail: [email protected]).

Abstract

Objective:

This study evaluated the relative bioavailability and pharmacokinetics of elvitegravir (EVG), emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), and a investigational pharmacoenhancer, cobicistat (GS-9350, COBI) coformulated as a fixed-dose combination tablet (FDC) compared with ritonavir-boosted EVG and FTC + TDF in healthy subjects.

Methods:

Subjects were randomized to 1 of 2 sequences. All treatments were administered in the morning for 10 days with food, separated by a 2-day washout. Blood samples were collected over 24 hours with the last dose of each treatment.

Results:

Forty-four subjects enrolled, 42 subjects completed all periods. All study treatments were generally well tolerated. Relative to ritonavir-boosted EVG, the geometric least-squares means ratios (GMR) [90% confidence interval (CI)] for EVG area under plasma concentration-time curve from time zero until the end of the dosing interval (AUC)tau, maximum concentration (_C_max), and trough concentration (_C_tau) were 118 (110 to 126), 108 (100 to 116), and 110 (95.3 to 127), respectively, with EVG/COBI 150 mg/FTC/TDF. Relative to FTC + TDF, FTC GMR, and 90% CI were 127 (115 to 140) for AUCtau, 121 (107 to 137) for _C_max, and 126 (118 to 136) for _C_tau; tenofovir (TFV) GMR and 90% CI were 118 (114 to 122), 130 (122 to 138), and 124 (119 to 129) for AUCtau, _C_max, and _C_tau, respectively, with EVG/COBI 150 mg/FTC/TDF.

Conclusions:

Fixed-dose combination tablet containing COBI 150 mg resulted in desired high EVG _C_tau concentrations and clinically equivalent tenofovir and FTC exposures relative to currently approved individual agents and was thus selected for subsequent evaluation.