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

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).

Copyright © 2018 Mehta et al.

Figures

FIG 1

Mean plasma concentrations of DTG (A) and RPV (B) plotted on a semilogarithmic scale by time after dosing. The main graphs show the plasma concentrations through the full PK sampling time course. Insets show expanded views of the shaded areas, which represent the first 24 h of PK sampling. The first concentration in each plot corresponds to the PK sampling at 0.5 h after dosing. Dotted gray lines denote the lower limits of quantification, which were 0.02 μg/ml for DTG and 0.001 μg/ml for RPV.

FIG 2

Two-way crossover study design. Cmax, maximum concentration of drug in plasma; CVw, within-participant coefficient of variation; DTG, dolutegravir; RPV, rilpivirine. a, the test treatment was an FDC tablet containing DTG at 50 mg and RPV at 25 mg; b, the reference treatment was separate tablets of DTG at 50 mg and RPV at 25 mg; c, sample size reestimation determined that ≥110 evaluable participants would be needed to maintain a 90% power; 118 participants were enrolled to maintain 90% power and account for the possibility of participant discontinuations.