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 [ 14 C]- 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. A single oral dose of [ 14 C]-Ainuovirine was administered to six healthy subjects. The drug was rapidly absorbed, with a T max of 3.42 hours, and exhibited a long terminal half-life (t½ of 43.5 h). Mass balance over 240 hours showed nearly complete recovery (101.64%), with excretion predominantly via the fecal route (73.54%), primarily as unchanged parent drug. The primary metabolic pathway involved CYP2C19-mediated mono-oxygenation to form metabolite M341, followed by glucuronidation. These comprehensive ADME data support ainuovirine's profile as a promising anchor agent for HIV-1 treatment.