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.

Additional Metadata
Persistent URL,
Journal Antiviral Therapy
Hotho, D.M, Bruijne, J, O'Farrell, N, Boyea, T, Li, J, Bracken, M, … Reesink, H.W. (2012). Pharmacokinetics and antiviral activity of PHX1766, a novel HCV protease inhibitor, using an accelerated Phase I study design. Antiviral Therapy, 17(2), 365–375. doi:10.3851/IMP1989