title: GSK1265744 pharmacokinetics in plasma and tissue after single-dose long-acting injectable administration in healthy subjects.
abstract: BACKGROUND
  GSK1265744 (744) is an HIV-1 integrase inhibitor in clinical development as a long-acting (LA) injectable formulation. This study evaluated plasma and tissue pharmacokinetics after single-dose administration of 744 LA administered by intramuscular (IM) or subcutaneous injections.
  
  
  METHODS
  This was a phase I, open-label, 9-cohort, parallel study of 744 in healthy subjects. 744 was administered as a 200 mg/mL nanosuspension at doses of 100-800 mg IM and 100-400 mg subcutaneous.
  
  
  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 pharmacokinetic sampling was performed for a minimum of 12 weeks or until 744 concentrations were ≤0.1 μg/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 after 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 after dosing. 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.
  
  
  CONCLUSIONS
  These data suggest 744 LA injection has potential application as a monthly or less frequent HIV treatment or prevention agent.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC.
authors.forename: William
authors.initials: W
authors.lastname: Spreen
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ford
authors.forename: Shuguang
authors.initials: S
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Wilfret
authors.forename: David
authors.initials: D
authors.lastname: Margolis
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gould
authors.forename: Stephen
authors.initials: S
authors.lastname: Piscitelli
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015331:Cohort Studies; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007267:Injections; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D011728:Pyridones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult; D054659:Diketopiperazines
chemical_list: D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations; D011728:Pyridones; C584914:cabotegravir; D054659:Diketopiperazines