title: Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults.
abstract: OBJECTIVE
  To evaluate the antiviral activity, safety, pharmacokinetics, and pharmacokinetics/pharmacodynamics of dolutegravir (DTG), a next-generation HIV integrase inhibitor (INI), as short-term monotherapy.
  
  
  METHODS
  A phase IIa, randomized, double-blind, dose-ranging study.
  
  
  METHODS
  In this study, INI-naive, HIV-1-infected adults currently off antiretroviral therapy were randomized to receive DTG (2, 10, or 50 mg) or placebo once daily for 10 days in an eight active and two placebo randomization scheme per DTG dose. Placebo patients were pooled for the purpose of analysis.
  
  
  RESULTS
  Thirty-five patients (n = 9 for DTG 2 and 10 mg, n = 10 for DTG 50 mg, and n = 7 for placebo) were enrolled. Baseline characteristics were similar across dose groups. Significant reductions in plasma HIV-1 RNA from baseline to day 11 were observed for all DTG dose groups compared with placebo (P < 0.001), with a mean decrease of 1.51-2.46 log(10) copies/ml. In addition, a well characterized dose-response relationship was observed for viral load decrease. Most patients (seven of 10, 70%) receiving DTG 50 mg achieved plasma HIV-1 RNA less than 50 copies/ml. The pharmacokinetic variability was low (coefficient of variation, range 25-50%). Plasma HIV-1 RNA reduction was best predicted by Cτ using an E(max) model. The most common adverse events were diarrhea, fatigue, and headache; the majority of adverse events were mild or moderate in severity.
  
  
  CONCLUSIONS
  Dolutegravir demonstrated potent antiviral activity, good short-term tolerability, low pharmacokinetic variability, and a predictable pharmacokinetics/pharmacodynamics relationship, which support once-daily dosing without a pharmacokinetic booster in integrase-naive patients in future studies.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina 27709, USA. sherene.s.min@gsk.com
authors.forename: Sherene
authors.initials: S
authors.lastname: Min
authors.forename: Louis
authors.initials: L
authors.lastname: Sloan
authors.forename: Edwin
authors.initials: E
authors.lastname: DeJesus
authors.forename: Trevor
authors.initials: T
authors.lastname: Hawkins
authors.forename: Lewis
authors.initials: L
authors.lastname: McCurdy
authors.forename: Ivy
authors.initials: I
authors.lastname: Song
authors.forename: Richard
authors.initials: R
authors.lastname: Stroder
authors.forename: Shuguang
authors.initials: S
authors.lastname: Chen
authors.forename: Mark
authors.initials: M
authors.lastname: Underwood
authors.forename: Tamio
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Stephen
authors.initials: S
authors.lastname: Piscitelli
authors.forename: Jay
authors.initials: J
authors.lastname: Lalezari
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D016896:Treatment Outcome; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir