Pharmacokinetics and safety of a new free-base formulation of tenofovir alafenamide 25 mg in healthy volunteers: A randomized, open-label, four-period, fully replicated crossover bioequivalence study

Purpose: This study compared the pharmacokinetic bioequivalence and safety of a new free-base formulation of 25 mg tenofovir alafenamide (TAF) to those of a reference formulation under fasting conditions. Patients and methods: In this phase I, randomized, open-label, two-sequence, four-period, fully replicated crossover trial, 48 healthy volunteers were enrolled to receive single doses of the test and reference formulations in the T-R-T-R or R-T-R-T sequences. The plasma concentrations of TAF and tenofovir were measured and analyzed using non-compartmental methods. As the TAF concentration exhibits high intra-individual variability, reference-scaled average bioequivalence can be applied. The safety and tolerability were monitored during the study. Results: All 48 volunteers received the study drug at least once. The pharmacokinetic analysis included 44 and 46 volunteers for TAF and tenofovir, respectively. The intra-individual coefficient of variation for the plasma maximum concentration (C _max ) of the reference TAF formulation was 59.86%, permitting an expanded acceptance range of 0.6984–1.4319. Both TAF and tenofovir met the bioequivalence criteria as the geometric mean ratios (test/reference) and 90% confidence intervals for the C _max and AUC _last of each substance were within 0.80–1.25. Both formulations were safe and well-tolerated, and no serious adverse events were observed. Conclusion: The novel free-base formulation of 25 mg TAF demonstrated pharmacokinetic bioequivalence with the reference formulation and was safe for use in healthy volunteers.