BACKGROUND & AIMS: Danoprevir (RG7227; ITMN-191) is a potent inhibitor of the HCV NS3/4A serine protease. The aims of this double-blind, placebo-controlled, multiple-ascending dose phase Ib study were to evaluate safety, tolerability, antiviral activity, resistance, and pharmacokinetics of once- and twice-daily danoprevir in the presence of low-dose ritonavir (danoprevir/r) and in combination with peginterferon alfa-2a (40KD)/ribavirin in treatment-naive HCV genotype 1 patients. METHODS:Thirty eligible patients were enrolled into three cohorts and treated withdanoprevir/r or placebo/r all in combination with peginterferon alfa-2a (40KD)/ribavirin for 15 days. Cohort 1 received danoprevir/r at 100/100mg twice daily; Cohort 2 200/100mg once daily; and Cohort 3 200/100mg twice daily. RESULTS: The median reductions in HCV RNA from baseline after 14 days of treatment (day 15) were -5.1, -4.8, and -4.6 log(10)IU/ml in Cohorts 1, 2, and 3, respectively, and -2.7 log(10) in placebo/r and peginterferon alfa-2a (40KD)/ribavirin recipients. Viral breakthrough was not observed in any patient. On day 15, HCV RNA was undetectable (<15IU/ml) in 6/9 (67%), 4/8 (50%), and 8/8 (100%) patients in Cohorts 1, 2, and 3, respectively. When co-administered with low dose ritonavir, danoprevir concentrations reached a steady state between 6 to 10 days of dosing. Danoprevir exposures increased more than dose proportionally between 100/100mg and 200/100mg. Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin was well-tolerated with no safety-related discontinuations. CONCLUSIONS:Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin provides profound and robust reductions in serum HCV RNA, at substantially lower systemic exposures compared to those observed with higher doses of danoprevir in the absence of ritonavir. These results support further studies of danoprevir/r.
RCT Entities:
BACKGROUND & AIMS:Danoprevir (RG7227; ITMN-191) is a potent inhibitor of the HCV NS3/4A serine protease. The aims of this double-blind, placebo-controlled, multiple-ascending dose phase Ib study were to evaluate safety, tolerability, antiviral activity, resistance, and pharmacokinetics of once- and twice-daily danoprevir in the presence of low-dose ritonavir (danoprevir/r) and in combination with peginterferon alfa-2a (40KD)/ribavirin in treatment-naive HCV genotype 1 patients. METHODS: Thirty eligible patients were enrolled into three cohorts and treated with danoprevir/r or placebo/r all in combination with peginterferon alfa-2a (40KD)/ribavirin for 15 days. Cohort 1 received danoprevir/r at 100/100mg twice daily; Cohort 2 200/100mg once daily; and Cohort 3 200/100mg twice daily. RESULTS: The median reductions in HCV RNA from baseline after 14 days of treatment (day 15) were -5.1, -4.8, and -4.6 log(10)IU/ml in Cohorts 1, 2, and 3, respectively, and -2.7 log(10) in placebo/r and peginterferon alfa-2a (40KD)/ribavirin recipients. Viral breakthrough was not observed in any patient. On day 15, HCV RNA was undetectable (<15IU/ml) in 6/9 (67%), 4/8 (50%), and 8/8 (100%) patients in Cohorts 1, 2, and 3, respectively. When co-administered with low dose ritonavir, danoprevir concentrations reached a steady state between 6 to 10 days of dosing. Danoprevir exposures increased more than dose proportionally between 100/100mg and 200/100mg. Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin was well-tolerated with no safety-related discontinuations. CONCLUSIONS:Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin provides profound and robust reductions in serum HCV RNA, at substantially lower systemic exposures compared to those observed with higher doses of danoprevir in the absence of ritonavir. These results support further studies of danoprevir/r.
Authors: Micaela B Reddy; Peter N Morcos; Sophie Le Pogam; Ying Ou; Karl Frank; Thierry Lave; Patrick Smith Journal: Antimicrob Agents Chemother Date: 2012-04-02 Impact factor: 5.191
Authors: Micaela B Reddy; Yuan Chen; Joshua O Haznedar; Jennifer Fretland; Steven Blotner; Patrick Smith; Jonathan Q Tran Journal: Clin Pharmacokinet Date: 2012-07-01 Impact factor: 6.447
Authors: Barbara J Brennan; Agnès Poirier; Sebastian Moreira; Peter N Morcos; Petra Goelzer; Renée Portmann; Jiney Asthappan; Christoph Funk; Patrick F Smith Journal: Clin Pharmacokinet Date: 2015-05 Impact factor: 6.447
Authors: Barbara J Brennan; Sebastian A Moreira; Peter N Morcos; Mercidita T Navarro; Jiney Asthappan; Petra Goelzer; Paul Weigl; Patrick F Smith Journal: Clin Pharmacokinet Date: 2013-09 Impact factor: 6.447
Authors: Edward J Gane; Régine Rouzier; Alicja Wiercinska-Drapalo; Dominique G Larrey; Peter N Morcos; Barbara J Brennan; Sophie Le Pogam; Isabel Nájera; Rosemary Petric; Jonathan Q Tran; Rohit Kulkarni; Ying Zhang; Patrick Smith; Ellen S Yetzer; Nancy S Shulman Journal: Antimicrob Agents Chemother Date: 2013-12-02 Impact factor: 5.191
Authors: Peter N Morcos; Linda Chang; Rohit Kulkarni; Mylene Giraudon; Nancy Shulman; Barbara J Brennan; Patrick F Smith; Jonathan Q Tran Journal: Eur J Clin Pharmacol Date: 2013-07-20 Impact factor: 2.953