title: Safety and pharmacokinetics of the HIV-1 protease inhibitor TMC310911 coadministered with ritonavir in healthy participants: results from 2 phase 1 studies.
abstract: OBJECTIVE
  To evaluate safety, tolerability, and pharmacokinetics of TMC310911, a novel human immunodeficiency virus type-1 protease inhibitor.
  
  
  METHODS
  Healthy participants aged 18-55 years with body mass index 18-30 kg/m were enrolled in 2 phase 1 studies. In the first-in-human, single-dose study, 18 participants received placebo or TMC310911 (75-2000 mg) in the double-blind phase and 8 participants received 300 or 600 mg of TMC310911 [administered alone or with 100 mg ritonavir twice daily (bid)] in the subsequent open-label phase. The multiple-dose double-blind study included 5 successive treatment sessions wherein healthy participants received placebo or TMC310911 [300 mg bid, 600 mg once daily or 150 mg bid (plus 100 mg ritonavir bid), 900 mg bid (alone) or 300 mg bid (plus ritonavir 50 mg bid)]; in all sessions, TMC310911 and ritonavir were administered for 6 and 9 days, respectively.
  
  
  RESULTS
  In the single-dose study, no dose-limiting toxicity was observed up to 2000 mg of TMC310911. Systemic exposure to TMC310911 generally increased in a dose-proportional manner after the single- or multiple-dose administrations. Coadministration of ritonavir increased the systemic exposure to TMC310911. The mean Cmax and area under plasma concentration-time curve values (single-dose: 1200 mg TMC310911) were higher under fasted conditions than in fed condition. In both studies, most treatment-emergent adverse events were related to gastrointestinal system.
  
  
  CONCLUSIONS
  TMC310911 exhibited a linear pharmacokinetic profile after the single- (up to 2000 mg) and multiple-dose (up to 900 mg) administrations; ritonavir improved the pharmacokinetic profile of TMC310911. TMC310911 was generally safe and tolerable when administered with or without ritonavir.
authors.affiliation: *Department of Research and Early Development, Janssen Infectious Diseases-Diagnostics BVBA, Beerse, Belgium; and †Department of Infectious Diseases, Janssen Research & Development, High Wycombe, United Kingdom.
authors.forename: Richard M W
authors.initials: RM
authors.lastname: Hoetelmans
authors.forename: Inge
authors.initials: I
authors.lastname: Dierynck
authors.forename: Ilham
authors.initials: I
authors.lastname: Smyej
authors.forename: Paul
authors.initials: P
authors.lastname: Meyvisch
authors.forename: Bert
authors.initials: B
authors.lastname: Jacquemyn
authors.forename: Kris
authors.initials: K
authors.lastname: Marien
authors.forename: Kenneth
authors.initials: K
authors.lastname: Simmen
authors.forename: Rene
authors.initials: R
authors.lastname: Verloes
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D010919:Placebos; D019438:Ritonavir