Background: GSK1265744 (744) is an HIV-1 integrase inhibitor (INI) in clinical development as a long-acting (LA) injectable formulation. This study evaluated plasma and tissue pharmacokinetics (PK) following single-dose administration of 744 LA administered by intramuscular (IM) or subcutaneous (SC) injections.
Methods: This was a Phase I, open-label, nine-cohort, parallel study of 744 in healthy subjects. 744 was administered as a 200 mg/mL nanosuspension at doses of 100 to 800 mg IM and 100 to 400 mg SC.
Results: Eight (6 active and 2 placebo) male and female subjects participated in each of the first 7 cohorts. All 8 subjects, 4 males and 4 females, received active 744 LA in Cohorts 8 and 9, and underwent rectal and cervicovaginal tissue sampling, respectively. Plasma PK sampling was performed for a minimum of 12 weeks or until 744 concentrations were <=0.1 [mu]g/mL. Rectal and cervicovaginal tissue biopsies were performed at Weeks 2 and 8 (Cohort 8) and Weeks 4 and 12 (Cohort 9). 744 LA was generally safe and well tolerated following single injections. A majority of subjects reported injection site reactions, all graded as mild in intensity. Plasma concentration-time profiles were prolonged with measureable concentrations up to 52 weeks post dose. 744 LA 800 mg IM achieved mean concentrations above protein adjusted-IC90 for approximately 16-weeks. Rectal and cervicovaginal tissue concentrations ranged from <8% to 28% of corresponding plasma concentrations.
Conclusion: These data suggest 744 LA injection has potential application as a monthly or less frequent HIV treatment or prevention agent.
(C) 2014 by Lippincott Williams & Wilkins