Absorption, distribution, metabolism, excretion and mass balance of ainuovirine, a non-nucleoside reverse transcriptase inhibitor in humans

This trial was a phase 1, single-centre, open-label pharmacokinetic, mass balance and biotransformation study to evaluate absorption, distribution, metabolism and excretion of radiolabelled ainuovirine, a novel non-nucleotide reverse transcriptase inhibitor, in healthy men. Six adults received a single dose of oral suspension containing [¹⁴C]- ainuovirine, at approximately 150 mg per 100 µCi. Pharmacokinetic parameters were derived from plasma total radioactivity. Mass balance was determined by measuring total radioactivity in plasma, whole blood, urine and faeces. The primary metabolic elimination pathway was characterised by analysing radioactive metabolite profiles in plasma, urine and faeces and the structures of major metabolites were identified. The results showed a C_max of 327 ng∙Eq./g; T_max of 3.42 h and t_½ of 43.5 h. The majority (>60 %) of the administered dose was excreted unchanged, primarily via faeces, within the 240-hour collection period. The mean cumulative recovery of total radioactivity was 101.64 %, with 28.10 % in urine and 73.54 % in faeces. Clearance was primarily mediated by CYP2C19 through mono-oxygenation of ainuovirine to form metabolite M341, followed by glucuronidation and subsequent excretion into faeces and urine. These findings, together with in vitro and in vivo pharmacology studies, support the consideration of ainuovirine as a desirable anchor antiretroviral agent for HIV-1 treatment.