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

What Is Known And Objective: 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.

Methods: After confirmation of tolerability and safety of oral doravirine, 36 participants were randomized 1:1:1 to receive IM doravirine 200 mg as Treatment A (1 × 1 mL, 20% [200 mg/mL] suspension), B (1 × 0.66 mL, 30% [300 mg/mL] suspension) or C (2 × 0.5 mL, 20% suspension). Blood samples were taken as venous plasma, venous dried blood spots (DBS) and fingerstick DBS.

Results And Discussion: Plasma concentration-time profiles following IM treatments demonstrated rapid initial doravirine release, with initial peak ~4 days post-injection, followed by decline over the next ~6 days; a second peak was reached at ~24-36 days, 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 (~46-58 days vs ~11-15 hours). 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.

What Is New And Conclusions: Novel doravirine LAP IM injection formulations investigated in this study demonstrated sustained plasma doravirine concentrations over a course of >20 weeks.