title: Pharmacokinetics and antiviral activity of PHX1766, a novel HCV protease inhibitor, using an accelerated Phase I study design.
abstract: BACKGROUND
  PHX1766 is a novel HCV NS3/4 protease inhibitor with robust potency and high selectivity in replicon studies (50% maximal effective concentration 8 nM). Two clinical trials investigated the safety, tolerability, pharmacokinetics and antiviral activity of PHX1766 in healthy volunteers (HV) and chronic hepatitis C patients, by use of a dose-adaptive overlapping clinical trial design.
  
  
  METHODS
  Two randomized, double-blind, placebo-controlled clinical trials were conducted. Single doses of PHX1766 or placebo were administered to 25 HV and six HCV genotype 1-infected patients (50 mg once daily -1,000 mg once daily, 250 mg twice daily and 100 mg of a new formulation of PHX1766 once daily). Multiple doses of PHX1766 or placebo were administered to 32 HV and seven HCV genotype 1-infected patients (50 mg once daily -800 mg twice daily).
  
  
  RESULTS
  Oral administration of PHX1766 was safe and well tolerated at all dose levels with rapid absorption (time at which concentration maximum is reached of 1-4 h) and with mean terminal half-lives of 4-23 h. Multiple doses of PHX1766 800 mg twice daily in HCV patients produced an area under the plasma concentration-time curve from time of drug administration to the last time point with a measurable concentration after dosing accumulation ratio of 2.3. The mean maximal observed HCV RNA decline was 0.6 log(10) IU/ml in the first 24 h in the single-dose protocol and 1.5 log(10) IU/ml after 6 days of PHX1766 dosing.
  
  
  CONCLUSIONS
  An overlapping, dose-adaptive single-dose and multiple-dose escalating design in HV and HCV-infected patients proved to be highly efficient in identifying a therapeutic dose. Although in vitro replicon studies indicated a robust HCV RNA viral decline of PHX1766, the study in HCV patients demonstrated only modest viral load reduction.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Daphne M
authors.initials: DM
authors.lastname: Hotho
authors.forename: Joep
authors.initials: J
authors.lastname: de Bruijne
authors.forename: A Marie
authors.initials: AM
authors.lastname: O'Farrell
authors.forename: Teresa
authors.initials: T
authors.lastname: Boyea
authors.forename: Jianke
authors.initials: J
authors.lastname: Li
authors.forename: Michele
authors.initials: M
authors.lastname: Bracken
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Campbell
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Guler
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Weegink
authors.forename: Janke
authors.initials: J
authors.lastname: Schinkel
authors.forename: Richard
authors.initials: R
authors.lastname: Molenkamp
authors.forename: Jeroen
authors.initials: J
authors.lastname: van de Wetering de Rooij
authors.forename: Andre
authors.initials: A
authors.lastname: van Vliet
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: de Knegt
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: Reesink
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001897:Boronic Acids / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004311:Double-Blind Method; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D007769:Lactams / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D001897:Boronic Acids; D007769:Lactams; C573714:PHX1766; D011480:Protease Inhibitors; D012367:RNA, Viral