Absorption, distribution, metabolism and excretion of ainuovirine in healthy adults: A radiolabelled mass balance and biotransformation study

Abstract

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Absorption, distribution, metabolism and excretion of ainuovirine in healthy adults: A radiolabelled mass balance and biotransformation study

Miao Liyan¹, Jiang Bin¹, Sang Shibiao¹, Qin Hong² and Wu Yuechan²

¹The First Affiliated Hospital of Soochow University; ²Jiangsu Aidea Pharmaceutical Co., Ltd

Background: Ainuovirine (ANV) is a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of human immunodeficiency virus type 1 (HIV-1) infection. The absorption, distribution, metabolism and elimination of ANV was evaluated in a human radiolabelled mass balance and biotransformation study.

Methods: A single-centre, single-dose, non-randomized, open-label study was conducted, in which six healthy males received a single dose of oral suspension containing [14C]ANV at 150 mg/approximately 100 μCi on the first day in the study under fasting condition. Whole blood, plasma, urine and faecal samples were collected at the specific time points during the study. The data of pharmacokinetic (PK) parameters of the total radioactivity in plasma, concentration ratio of total radioactivity in whole blood to plasma and mass balance were obtained by measuring the total radioactivity of [14C]ANV in plasma, whole blood, urine and faeces. The main metabolic elimination pathways and characteristics of ANV in human body were obtained by analysing the radioactive metabolite profiles in plasma, urine and faeces; and the structure of major metabolites was identified using radioisotope and mass spectrometry.

Results: The time to maximum plasma total radioactivity (T_max) was 3.42 h; the mean maximum concentration (C_max) was 327 ng·eq./g; and the half-life of the total radioactivity terminal elimination phase (t½) was 43.5 h. Within 0–240 h, the mean cumulative excretion rate of total radioactivity was 101.64%. Specifically, the mean total excretion accounted for 28.10% of the administered dose in urine and 73.54% of the administered dose in faeces, suggesting that [14C]ANV was primarily excreted into faeces. The primary clearance pathway of [14C]ANV was mono-oxygenated to form M341, which was further glucuronidated, and metabolized by the liver, and excreted into faeces and urine. The secondary metabolic pathway was glucuronidation of the unchanged drug to form M501, which was excreted into urine.

Conclusions: Ainuovirine is primarily metabolized by the liver and excreted into faeces and urine, with a low plasma clearance, in the human body.

Keywords: ainuovirine, human immunodeficiency virus 1, mass balance, non-nucleoside reverse transcriptase inhibitor, pharmacokinetics