Randomized Trial of Food Effect on Pharmacokinetic Parameters of ABX464 Administered Orally to Healthy Male Subjects

Abstract

ABX464 is an antiviral that provides a novel approach to the reduction and control of HIV infection. Investigation of food influence is important in the optimization of treatment. An open-label, food effect, randomized study which included 2 groups of 24 subjects each was carried out to assess the bioavailability and safety of single (group 1) and repeated (group 2) oral doses of ABX464 (50 mg) under fed or fasted conditions. The maximum concentration (C max ) and the area under the concentration-time curve from time zero to infinity (AUC 0 -∞ ) of ABX464 were demonstrated to increase with food after a single dose of ABX464 (219% and 188%, respectively). The apparent terminal elimination half-lives (t 1/2 s) under fed and fasted conditions were comparable, at about 0.80 h. The median time to maximum concentration (T max ) was delayed from 1.5 to 2.8 h, and the ratio of the AUC 0 -∞ obtained under fed conditions to the AUC 0 -∞ obtained under fasted conditions (F rel ) was 2.69. Comparable results were obtained on day 1 and day 10 in group 2. The increases in C max and AUC 0 -∞ of the metabolite ABX464 -N-glucuronide (ABX464-NGlc) were, however, much more limited when ABX464 was given with food. The t 1/2 s were also comparable under the two conditions (around 100 h). Between day 1 and day 10, the C max increased by 5% under the fasted condition and by 25% under the fed condition. The most common related treatment-emergent adverse events were headaches, vomiting, and nausea. It was concluded that food has a significant impact on the levels of ABX464 in plasma with a delay in absorption and increased relative bioavailability, with a lesser impact on its biotransformation into ABX464-NGlc. ABX464 was well tolerated under both fasted and fed conditions. (This study has been registered at ClinicalTrials.gov under registration no. NCT02731885.)

Safety, Pharmacokinetics, and Antiviral Activity of a Novel HIV Antiviral, ABX464, in Treatment-Naive HIV-Infected Subjects in a Phase 2 Randomized, Controlled Study

“…This study demonstrated that there were no substantial differences in the PK characteristics of the two compounds between HIV-infected and non-HIV-infected subjects. It was also confirmed that the food effect of both compounds was comparable to that reported in noninfected subjects ( 14 ).…”

“…In these studies, whereas HAART was very efficient in reducing the viral load to undetectable levels after 2 to 3 weeks in all treated mice, only 30% of mice treated with ABX464 had an undetectable viral load after the same treatment period, and longer treatment with ABX464 was required to achieve a viral load reduction in more mice. In addition, the PK data reported here and in previous studies demonstrated that the parent compound has a very short half-life of approximately 1 h compared to the metabolite ABX464-NGlc, which has a t 1/2 of approximately 100 h ( 13 , 14 ). The maximum concentration in plasma ( C max ) of the metabolite was also approximately 160-fold higher than that of the parent compound.…”

“…The data obtained for both ABX464 and ABX464-NGlc in HIV-infected subjects demonstrated no differences in key PK characteristics compared to those previously reported in healthy non-HIV-infected subjects ( 13 , 14 ). ABX464 was rapidly eliminated with a half-life ( t 1/2 ) of about 1 h, while its metabolite, ABX464-NGlc, was very slowly cleared with a t 1/2 of about 100 h. Data comparing the key PK characteristics of ABX464 for one dose regimen in HIV-infected subjects from this study and healthy non-HIV-infected subjects from a previous study ( 13 ) are presented in Table S1 in the supplemental material.…”

“…A second study in healthy volunteers to evaluate the impact of food consumption and repeated dosing on ABX464 pharmacokinetic properties and biological safety has also been completed, and this has confirmed the good tolerability profile of the product ( 14 ). The present study (ClinicalTrials.gov registration no.…”

“…The pharmacokinetic profiles of ABX464 and its main metabolite, ABX464-NGlc, have previously been extensively studied but only in healthy, non-HIV-infected subjects ( 13 , 14 ). This study demonstrated that there were no substantial differences in the PK characteristics of the two compounds between HIV-infected and non-HIV-infected subjects.…”