Pharmacokinetics, safety and tolerability of long-acting parenteral intramuscular injection formulations of doravirine.

Abstract

Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus (HIV)-1 infection. This phase 1 study in healthy adults investigated the pharmacokinetics, safety and tolerability of long-acting parenteral (LAP) microsuspension formulations of doravirine administered as an intramuscular (IM) injection. After confirmation of tolerability and safety of oral doravirine, 36 participants were randomized 1:1:1 to receive IM doravirine 200mg as TreatmentA (1×1mL, 20% [200mg/mL] suspension), B (1×0.66mL, 30% [300mg/mL] suspension) or C (2×0.5mL, 20% suspension). Blood samples were taken as venous plasma, venous dried blood spots (DBS) and fingerstick DBS. Plasma concentration-time profiles following IM treatments demonstrated rapid initial doravirine release, with initial peak ~4days post-injection, followed by decline over the next ~6days; a second peak was reached at ~24-36days, corresponding to prolonged and sustained release, with measurable concentrations up to Day 183. Treatment C was associated with highest peak concentrations and shortest time to maximum concentration. Elimination half-lives for all IM formulations were prolonged versus oral administration (~46-58days vs ~11-15hours). Oral doravirine and IM doravirine were generally well tolerated; injection-site pain was the most common adverse event for IM doravirine. Doravirine concentrations from DBS samples showed strong correlations to venous plasma concentrations. Novel doravirine LAP IM injection formulations investigated in this study demonstrated sustained plasma doravirine concentrations over a course of >20weeks.