title: Pharmacokinetics, safety, and tolerability with repeat doses of GSK1265744 and rilpivirine (TMC278) long-acting nanosuspensions in healthy adults.
abstract: 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 Three subjects discontinued during injection phase (consent withdrawn, n = 2; self-limited rash, n = 1).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.
authors.affiliation: *GlaxoSmithKline, Infectious Diseases Research & Development, Research Triangle Park, NC; and †Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: William
authors.initials: W
authors.lastname: Spreen
authors.forename: Peter
authors.initials: P
authors.lastname: Williams
authors.forename: David
authors.initials: D
authors.lastname: Margolis
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ford
authors.forename: Herta
authors.initials: H
authors.lastname: Crauwels
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Gould
authors.forename: Marita
authors.initials: M
authors.lastname: Stevens
authors.forename: Stephen
authors.initials: S
authors.lastname: Piscitelli
mesh_terms: D000293:Adolescent; D000328:Adult; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011728:Pyridones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000068696:Rilpivirine; D055815:Young Adult; D054659:Diketopiperazines
chemical_list: D003692:Delayed-Action Preparations; D009570:Nitriles; D011728:Pyridones; D011743:Pyrimidines; D000068696:Rilpivirine; C584914:cabotegravir; D054659:Diketopiperazines