Pharmacokinetics, safety, and tolerability with repeat doses of GSK1265744 and rilpivirine (TMC278) long-acting nanosuspensions in healthy adults

• Published in: Journal of acquired immune deficiency syndromes (1999) Vol. 67; no. 5; p. 487
• Main Authors: Spreen, William, Williams, Peter, Margolis, David, Ford, Susan L, Crauwels, Herta, Lou, Yu, Gould, Elizabeth, Stevens, Marita, Piscitelli, Stephen
• Format: Journal Article
• Language: English
• Published: United States 15.12.2014
• Subjects: Adolescent; Adult; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - adverse effects; Delayed-Action Preparations - pharmacokinetics; Drug Therapy, Combination - adverse effects; Drug Therapy, Combination - methods; Female; Humans; Injections, Intramuscular; Injections, Subcutaneous; Male; Middle Aged; Nitriles - administration & dosage; Nitriles - adverse effects; Nitriles - pharmacokinetics; Pyridones - administration & dosage; Pyridones - adverse effects; Pyridones - pharmacokinetics; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Rilpivirine; Young Adult
• ISSN: 1944-7884
• DOI: 10.1097/QAI.0000000000000365

Pharmacokinetics, safety, and tolerability of GSK1265744 (744) and rilpivirine (RPV) (TMC278) were assessed after repeat dosing of long-acting (LA) injectable formulations in healthy subjects. Subjects received a 14-day lead-in of oral 744 (30 mg/d) to assess safety and tolerability before injectable administration. Subjects were randomized into 4 cohorts: 800 mg of 744 LA intramuscularly (IM) followed by 3 monthly doses of (1) 200 mg subcutaneously, (2) 200 mg IM, (3) 400 mg IM, or (4) a second injection of 800 mg IM after 12 weeks. Cohorts 2 and 3 also received IM doses of RPV LA at months 3 (1200 mg) and 4 (900 or 600 mg). Pharmacokinetics and safety were assessed throughout the trial. Forty-seven subjects enrolled; 40 received ≥1 LA injection with 37 completing all planned injections. Seven subjects discontinued 744 oral (non-drug-related, n = 6; dizziness, n = 1). The 744 LA and RPV LA injections were generally well tolerated, with grade 1 injection site reactions most commonly reported. Three subjects discontinued during injection phase (consent withdrawn, n = 2; self-limited rash, n = 1). There were no grade 3 or 4 adverse events and no clinically significant trends in laboratory abnormalities, electrocardiograms, or vital signs. All dose cohorts achieved therapeutically relevant plasma concentrations of each drug within 3 days with prolonged exposure over the dosing interval. Plasma concentrations of 744 exceeded the protein-adjusted IC90 and RPV plasma concentrations and were comparable to steady-state oral RPV 25 mg/d. These data support the potential application of dual-therapy 744 LA and RPV LA for treatment of HIV-1 infection.