Safety, tolerability and pharmacokinetics of rilpivirine following administration of a long‐acting formulation in healthy volunteers

• Published in: HIV medicine Vol. 16; no. 8; pp. 477 - 484
• Main Authors: Verloes, R, Deleu, S, Niemeijer, N, Crauwels, H, Meyvisch, P, Williams, P
• Format: Journal Article
• Language: English
• Published: England 01.09.2015
• Subjects: Adult; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - adverse effects; Anti-HIV Agents - pharmacokinetics; Area Under Curve; Delayed-Action Preparations; Double-Blind Method; Female; Healthy Volunteers; HIV; HIV Infections - drug therapy; Humans; long‐acting formulation; Male; Middle Aged; nonnucleoside reverse transcriptase inhibitor; pharmacokinetics; Reverse Transcriptase Inhibitors - administration & dosage; Reverse Transcriptase Inhibitors - adverse effects; Reverse Transcriptase Inhibitors - pharmacokinetics; rilpivirine; Rilpivirine - administration & dosage; Rilpivirine - adverse effects; Rilpivirine - pharmacokinetics; Young Adult; nonnucleoside reverse transcriptase inhibitor; pharmacokinetics; HIV; long-acting formulation; rilpivirine
• ISSN: 1464-2662; 1468-1293
• DOI: 10.1111/hiv.12247

Objectives This phase I healthy volunteer study (NCT01031589) was carried out to investigate the safety/tolerability and pharmacokinetics of a rilpivirine (RPV; TMC278) long‐acting (LA) formulation after single and multiple intramuscular (IM) injections. Methods In the first part of the study, which had an open‐label design, a single RPV LA IM injection (300 mg/mL) of 300 (n = 6) or 600 (n = 5) mg was given to the volunteers. In the second part of the study, which had a double‐blind, randomized, placebo‐controlled design, three RPV LA IM injections (one every 4 weeks) at 1200/600/600 mg (n = 6) or placebo (n = 2) were given. Safety and local tolerability were monitored. RPV plasma concentrations were analysed up to 28 days after injection or until they were < 20 ng/mL. Results Grade 1/2 RPV‐related adverse events in the 300, 600 and 1200/600/600 mg groups were: rash (zero, one and one subject, respectively, the last of whom discontinued participation in the study); musculoskeletal stiffness (three, zero and zero subjects, respectively); injection site reactions (one, two and two subjects, respectively). After one injection of 300, 600 or 1200 mg RPV LA, the mean (standard deviation) maximum plasma concentration was 39 (25), 48 (13) and 140 (16) ng/mL, and the mean (standard deviation) area under the concentration–time curve (28 days) was 17 090 (8907), 25 240 (8184) and 55 350 (13 550) ng h/mL, respectively. RPV pharmacokinetics were largely comparable after the 1200 mg loading dose and both 600 mg injections of RPV LA. The mean (standard deviation) RPV plasma concentration across the 28‐day dosing interval after the last injection in the 1200/600/600 mg group was 79 (19) ng/mL. Conclusions Single and multiple IM injections of RPV LA demonstrated favourable local/systemic tolerability in healthy volunteers. RPV pharmacokinetics suggested that clinically relevant plasma concentrations can be achieved with this LA formulation.