期刊
JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES
卷 67, 期 5, 页码 487-492出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAI.0000000000000365
关键词
long-acting; GSK1265744; rilpivirine; TMC278; injections; pharmacokinetics; nanosuspension
资金
- ViiV Healthcare
- Janssen Research Development
Objective: 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. Methods: 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. Results: 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 Three subjects discontinued during injection phase (consent withdrawn, n = 2; self-limited rash, n = 1).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. Conclusions: These data support the potential application of dual-therapy 744 LA and RPV LA for treatment of HIV-1 infection.
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