A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV [electronic resource]

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Tác giả:

Ngôn ngữ: eng

Ký hiệu phân loại: 615.3 Organic drugs

Thông tin xuất bản: Los Alamos, N.M. : Oak Ridge, Tenn. : Los Alamos National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2014

Mô tả vật lý: Size: p. 469-477 : , digital, PDF file.

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ID: 262124

 Background?Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct acting antivirals (DAAs). 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 1 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-na�ve and 8 were non-responders to prior PEG-IFN-?/ribavirin treatment. Results?In most 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. We found 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 bid) and 0.99 at the highest dose (200 mg tid). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg bid). Finally, the second phase decline showed two different behaviors, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>
 0.3 d-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.
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