Single-ascending dose and food effect studies to assess safety and pharmacokinetics of ainuovirine, a novel non-nucleoside reverse transcriptase inhibitor, for treatment of HIV-1 infection

Abstract

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Single-ascending dose and food effect studies to assess safety and pharmacokinetics of ainuovirine, a novel non-nucleoside reverse transcriptase inhibitor, for treatment of HIV-1 infection

Su Bin¹, Wu Hao¹, Wang Meixia¹, Yang Juan², Yun Xinming² and Qin Hong²

¹Beijing Youan Hospital Affiliated to Capital Medical University; ²Jiangsu Aidea Pharmaceutical Co., Ltd

Background: Ainuovirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of HIV-1 infection. This first-in-human study was conducted to characterize the tolerability, pharmacokinetics and food effect of single-ascending oral doses of ainuovirine in healthy adults.

Methods: In the single-dose escalation study, three cohorts of each 10 participants, aged from 18 to 45 years, were randomly allocated to receive a single-dose ainuovirine 75, 150 or 300 mg, respectively. Inhibitory quotient (IQ) was defined as the ratio of the clinical trough concentration (C24h) to the 50% effective concentration (EC50). In the food effect study, 16 participants were equally assigned to a randomized, open-label, two-period crossover study and received a single oral dose of ainuovirine 150 mg in the fasting state or after a high-fat meal, with a 14-day washout period between periods.

Results: Ainuovirine was well tolerated. Across all dosage groups, most adverse events were rated as mild in severity. Ainuovirine was readily absorbed, with a median T_max of approximately 3 h. Ainuovirine exposure (C_max and AUC) increased to a lesser extent than the dose proportionality. Median apparent terminal half-life (T1/2z) remained similar across three dose cohorts, slightly longer than 24 h. The IQs for wild type (EC50 = 2.2 ng/mL) were 36.4-, 51.7- and 61.0-fold, respectively; 5.2-, 7.4- and 8.8-fold for K103N mutant (EC50 = 15.3 ng/mL), respectively; and 3.6, 5.1 and 6.1 folds for Y181C mutant (EC50 = 22.1 ng/mL), respectively. The geometric mean ratios of C_max, AUC_0–t and AUC_0–∞ in fed/fasting state were 190.07%, 136.73% and 141.71% respectively, with 90% CI of 169.52%–213.12%, 128.32%–145.69% and 131.59%–152.61%. The food effect of ainuovirine was evaluated clinically not significant.

Conclusion: Ainuovirine was well tolerated and showed a dose-dependent, non-linear pharmacokinetics, eliciting no dose-limiting toxicity in healthy volunteers. Clinically insignificant food effect required no restriction in dosing without meal.

Keywords: ainuovirine, food effect, pharmacokinetics