BACKGROUND: Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct-acting antivirals. METHODS: We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a Phase I study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naive and 8 were non-responders to prior pegylated IFN-α/ribavirin treatment. RESULTS: In all patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VK model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. The antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg twice daily) and 0.99 at the highest dose (200 mg three times daily). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg twice daily). The second phase decline showed two different behaviours, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 day(-1)), whereas the viral decline was slower in the other patients. CONCLUSIONS: Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.
BACKGROUND: Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct-acting antivirals. METHODS: We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a Phase I study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naive and 8 were non-responders to prior pegylated IFN-α/ribavirin treatment. RESULTS: In all patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VK model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. The antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg twice daily) and 0.99 at the highest dose (200 mg three times daily). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg twice daily). The second phase decline showed two different behaviours, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 day(-1)), whereas the viral decline was slower in the other patients. CONCLUSIONS: Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.
Authors: Fred Poordad; Jonathan McCone; Bruce R Bacon; Savino Bruno; Michael P Manns; Mark S Sulkowski; Ira M Jacobson; K Rajender Reddy; Zachary D Goodman; Navdeep Boparai; Mark J DiNubile; Vilma Sniukiene; Clifford A Brass; Janice K Albrecht; Jean-Pierre Bronowicki Journal: N Engl J Med Date: 2011-03-31 Impact factor: 91.245
Authors: Jeremie Guedj; Harel Dahari; Libin Rong; Natasha D Sansone; Richard E Nettles; Scott J Cotler; Thomas J Layden; Susan L Uprichard; Alan S Perelson Journal: Proc Natl Acad Sci U S A Date: 2013-02-19 Impact factor: 11.205
Authors: Edward J Gane; Paul J Pockros; Stefan Zeuzem; Patrick Marcellin; Anna Shikhman; Coen Bernaards; Julian Zhou; Ellen S Yetzer; Rosa Ballester; Cindy Dwyer; Xiao Tong; Isabel Nájera; Anne Bertasso; Janet Hammond; Amy Kindrick; Peter N Morcos; Patrick Smith; Saray Stancic; Nancy S Shulman Journal: Liver Int Date: 2014-06-19 Impact factor: 5.828
Authors: Edward J Gane; Catherine A Stedman; Robert H Hyland; Xiao Ding; Evguenia Svarovskaia; William T Symonds; Robert G Hindes; M Michelle Berrey Journal: N Engl J Med Date: 2013-01-03 Impact factor: 91.245