A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV
Abstract
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-naïve and 8 were non-responders to prior PEG-IFN-α/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 rapidmore »
- Authors:
-
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics; Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Center for Nonlinear Studies; Univ. of Colorado, Boulder, CO (United States). Dept. of Chemical and Biological Engineering
- Inst. for Medical Research (INSERM), Paris (France). Infection Antimicrobials Modelling Evolution (IAME); Univ. Paris Diderot, Paris (France)
- Roche, Basel (Switzerland). Pharma Development, Methodology and Innovation Dept.
- Roche, Nutley, NJ (United States). Clinical Pharmacology, Pharma Research and Early Development
- d3 Medicine, Montville, NJ (United States); Univ. at Buffalo, NY (United States). School of Pharmacy and Pharmaceutical Sciences
- Publication Date:
- Research Org.:
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH)
- OSTI Identifier:
- 1282103
- Grant/Contract Number:
- AC52-06NA25396; R01-AI028433; P20-GM103452; R01-HL109334; R01-AI078881; R01-OD011095
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Antiviral Therapy
- Additional Journal Information:
- Journal Volume: 20; Journal Issue: 5; Journal ID: ISSN 1359-6535
- Publisher:
- International Medical Press
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Canini, Laetitia, Chatterjee, Anushree, Guedj, Jeremie, Lemenuel-Diot, Annabelle, Brennan, Barbara, Smith, Patrick F., and Perelson, Alan S. A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV. United States: N. p., 2014.
Web. doi:10.3851/imp2879.
Canini, Laetitia, Chatterjee, Anushree, Guedj, Jeremie, Lemenuel-Diot, Annabelle, Brennan, Barbara, Smith, Patrick F., & Perelson, Alan S. A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV. United States. https://doi.org/10.3851/imp2879
Canini, Laetitia, Chatterjee, Anushree, Guedj, Jeremie, Lemenuel-Diot, Annabelle, Brennan, Barbara, Smith, Patrick F., and Perelson, Alan S. Thu .
"A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV". United States. https://doi.org/10.3851/imp2879. https://www.osti.gov/servlets/purl/1282103.
@article{osti_1282103,
title = {A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV},
author = {Canini, Laetitia and Chatterjee, Anushree and Guedj, Jeremie and Lemenuel-Diot, Annabelle and Brennan, Barbara and Smith, Patrick F. and Perelson, Alan S.},
abstractNote = {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-naïve and 8 were non-responders to prior PEG-IFN-α/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.},
doi = {10.3851/imp2879},
journal = {Antiviral Therapy},
number = 5,
volume = 20,
place = {United States},
year = {Thu Oct 16 00:00:00 EDT 2014},
month = {Thu Oct 16 00:00:00 EDT 2014}
}
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