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Antimicrob Agents Chemother. 2018 Aug 27;62(9). pii: e00748-18. doi: 10.1128/AAC.00748-18. Print 2018 Sep.

Bioequivalence of a Fixed-Dose Combination Tablet of the Complete Two-Drug Regimen of Dolutegravir and Rilpivirine for Treatment of HIV-1 Infection.

Author information

1
GlaxoSmithKline, Research Triangle Park, North Carolina, USA rashmi.s.mehta@gsk.com.
2
GlaxoSmithKline, Collegeville, Pennsylvania, USA.
3
PAREXEL International, Durham, North Carolina, USA.
4
GlaxoSmithKline, QSI, Bengaluru, Karnataka, India.
5
Janssen Research and Development, Beerse, Belgium.
6
GlaxoSmithKline, Brentford, Middlesex, United Kingdom.
7
ViiV Healthcare, Collegeville, Pennsylvania, USA.
8
ViiV Healthcare, Research Triangle Park, North Carolina, USA.

Abstract

A complete 2-drug regimen of dolutegravir at 50 mg and rilpivirine at 25 mg was approved to treat HIV-1 infection in virologically suppressed patients after demonstrating acceptable efficacy and tolerability. This study investigated the bioequivalence and pharmacokinetics of the fixed-dose combination tablet compared with those of separate tablets. Secondary endpoints were the tolerability and safety of the fixed-dose combination tablet. In this open-label, randomized-sequence, 2-way crossover trial, single doses of the fixed-dose combination tablet (the test treatment) and the combination of separate tablets (the reference treatment) were administered to healthy adults after a moderate-fat meal, with a 21-day washout between treatments. Pharmacokinetic samples were collected through 12 days after dosing. The primary endpoints were the area under the plasma concentration-time curve (AUC) and the maximum concentration of drug in plasma (Cmax). The study employed a prespecified sample size reestimation based on a blind midpoint review of Cmax variability to update the enrollment size to achieve statistical power. Of 118 participants enrolled, 113 received both treatments and underwent pharmacokinetic assessment. The 90% confidence intervals for the geometric least-squares mean ratios for the AUC from 0 h to infinity, the AUC from 0 h to the last quantifiable measurement, and Cmax (test treatment versus reference treatment) were within the bioequivalence range of 0.80 to 1.25 for both drugs, indicating bioequivalence. In this study, a single dose of either treatment was well tolerated overall, with 4% (n = 5) and 3% (n = 3) of participants reporting adverse events considered related to the test and reference treatments, respectively. The dolutegravir-rilpivirine fixed-dose combination tablet is bioequivalent to a combination of separate tablets, and no new safety signals emerged. (This study has been registered at ClinicalTrials.gov under identifier NCT02741557.).

KEYWORDS:

bioequivalence; dolutegravir; fixed-dose combination (FDC); integrase strand transfer inhibitor (INSTI); nonnucleoside reverse transcriptase inhibitor (NNRTI); pharmacokinetics; rilpivirine; two-drug regimen (2DR)

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