title: Safety, tolerability and pharmacokinetics of rilpivirine following administration of a long-acting formulation in healthy volunteers.
abstract: OBJECTIVE
  This phase I healthy volunteer study (NCT01031589) was carried out to investigate the safety/tolerability and pharmacokinetics of a rilpivirine (RPV; TMC278) long-acting (LA) formulation after single and multiple intramuscular (i.m.) injections.
  
  
  METHODS
  In the first part of the study, which had an open-label design, a single RPV LA i.m. injection (300 mg/mL) of 300 (n = 6) or 600 (n = 5) mg was given to the volunteers. In the second part of the study, which had a double-blind, randomized, placebo-controlled design, three RPV LA i.m. injections (one every 4 weeks) at 1200/600/600 mg (n = 6) or placebo (n = 2) were given. Safety and local tolerability were monitored. RPV plasma concentrations were analysed up to 28 days after injection or until they were < 20 ng/mL.
  
  
  RESULTS
  Grade 1/2 RPV-related adverse events in the 300, 600 and 1200/600/600 mg groups were: rash (zero, one and one subject, respectively, the last of whom discontinued participation in the study); musculoskeletal stiffness (three, zero and zero subjects, respectively); injection site reactions (one, two and two subjects, respectively). After one injection of 300, 600 or 1200 mg RPV LA, the mean (standard deviation) maximum plasma concentration was 39 (25), 48 (13) and 140 (16) ng/mL, and the mean (standard deviation) area under the concentration-time curve (28 days) was 17,090 (8907), 25,240 (8184) and 55,350 (13,550) ng h/mL, respectively. RPV pharmacokinetics were largely comparable after the 1200 mg loading dose and both 600 mg injections of RPV LA. The mean (standard deviation) RPV plasma concentration across the 28-day dosing interval after the last injection in the 1200/600/600 mg group was 79 (19) ng/mL.
  
  
  CONCLUSIONS
  Single and multiple i.m. injections of RPV LA demonstrated favourable local/systemic tolerability in healthy volunteers. RPV pharmacokinetics suggested that clinically relevant plasma concentrations can be achieved with this LA formulation.
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Verloes
authors.affiliation: Janssen Clinical Pharmacology Unit, Merksem, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Deleu
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: N
authors.initials: N
authors.lastname: Niemeijer
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Crauwels
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Meyvisch
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Williams
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000068696:Rilpivirine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D003692:Delayed-Action Preparations; D018894:Reverse Transcriptase Inhibitors; D000068696:Rilpivirine
keywords: HIV; long-acting formulation; nonnucleoside reverse transcriptase inhibitor; pharmacokinetics; rilpivirine