title: Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor.
abstract: BACKGROUND
  GSK1265744 is an HIV integrase strand transfer inhibitor selected for clinical development.
  
  
  OBJECTIVE
  This first-time-in-human and phase IIa investigation assessed GSK1265744 antiviral activity, pharmacokinetics, safety, and tolerability in healthy and HIV-1-infected subjects.
  
  
  METHODS
  This double-blind, placebo-controlled study consisted of a dose escalation of single (part A) and multiple (part B) oral doses in 48 healthy subjects and an oral dose (part C) in 11 HIV-1-infected subjects. In part A, 2 cohorts of 9 subjects received either 5 and 25 mg or 10 and 50 mg. In part B, 3 cohorts of 10 subjects received 5, 10, or 25 mg once daily for 14 days. In part C and the phase IIa study, subjects received 5 or 30 mg once daily for 10 days.
  
  
  RESULTS
  Dose-proportional increases in drug exposure were observed in healthy and HIV-1-infected subjects. In healthy subjects, pharmacokinetic variability was low following single or repeat dosing (coefficient of variation, 13%-34% and 15%-23%, respectively). Mean plasma half-life was 31.5 hours. GSK1265744 monotherapy significantly reduced plasma HIV-1 RNA from baseline to day 11 in HIV-1-infected subjects receiving 5 or 30 mg versus placebo (P < .001); mean decrease was 2.2 to 2.3 log10 copies/mL, respectively. Study drug was generally well tolerated with no clinically relevant trends in laboratory values, vital signs, or electrocardiograms.
  
  
  CONCLUSIONS
  GSK1265744 was well tolerated in healthy and HIV-1-infected subjects. Results demonstrate once-daily doses of 5 or 30 mg exceeded minimum target therapeutic concentrations and produced a significant reduction in plasma HIV-1 RNA viral load.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: W
authors.initials: W
authors.lastname: Spreen
authors.forename: S
authors.initials: S
authors.lastname: Min
authors.forename: S L
authors.initials: SL
authors.lastname: Ford
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Lou
authors.forename: M
authors.initials: M
authors.lastname: Bomar
authors.forename: M
authors.initials: M
authors.lastname: St Clair
authors.forename: S
authors.initials: S
authors.lastname: Piscitelli
authors.forename: T
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D011728:Pyridones / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012367:RNA, Viral; D019562:Viral Load; D055815:Young Adult; D054659:Diketopiperazines
chemical_list: D019380:Anti-HIV Agents; D011728:Pyridones; D012367:RNA, Viral; C584914:cabotegravir; D054659:Diketopiperazines
keywords: GSK1265744; HIV integrase inhibitor; HIV-1; antiretroviral agent; dose-response relationship; pharmacokinetics