Modelling the interaction between danoprevir and mericitabine in the treatment of chronic HCV infection

Canini, Laetitia; Guedj, Jeremie; Chatterjee, Anushree; Lemenuel-Diot, Annabelle; Smith, Patrick F.; Perelson, Alan S.

doi:10.3851/IMP3006

Title: Modelling the interaction between danoprevir and mericitabine in the treatment of chronic HCV infection

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Abstract

In this study, modelling HCV RNA decline kinetics under therapy has proven useful for characterizing treatment effectiveness. Here we model HCV viral kinetics (VK) in 72 patients given a combination of danoprevir, a protease inhibitor, and mericitabine, a nucleoside polymerase inhibitor, for 14 days in the INFORM-1 trial. A biphasic VK model with time-varying danoprevir and mericitabine effectiveness and Bliss independence for characterizing the interaction between both drugs provided the best fit to the VK data. As a result, the average final antiviral effectiveness of the drug combination varied between 0.998 for 100 mg three times daily of danoprevir and 500 mg twice daily of mericitabine and 0.9998 for 600 mg twice daily of danoprevir and 1,000 mg twice daily of mericitabine. Using the individual parameters estimated from the VK data collected over 2 weeks, we were not able to reproduce the low sustained virological response rates obtained in a more recent study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir for 24 weeks. In conclusion, this suggests that drug-resistant viruses emerge after 2 weeks of treatment and that longer studies are necessary to provide accurate predictions of longer treatment outcomes.

Authors:

Canini, Laetitia ^[1]; Guedj, Jeremie ^[2]; Chatterjee, Anushree ^[3]; Lemenuel-Diot, Annabelle ^[4]; Smith, Patrick F. ^[5]; Perelson, Alan S. ^[6]

Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. of Edinburgh (United Kingdom)
Univ. Paris Diderot, Paris (France); INSERM, UMR 1137, Paris (France)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. of Colorado, Boulder, CO (United States)
Pharma Development, Basel (Switzerland)
d3 Medicine, Montville, NJ (United States); Univ. at Buffalo, Buffalo, NY (United States)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Publication Date:: Thu Jan 01 00:00:00 EST 2015

Research Org.:: Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Sponsoring Org.:: National Institutes of Health (NIH); USDOE

OSTI Identifier:: 1324566

Report Number(s):: LA-UR-15-22901
Journal ID: ISSN 1359-6535

Grant/Contract Number:: AC52-06NA25396

Resource Type:: Accepted Manuscript

Journal Name:: Antiviral Therapy

Additional Journal Information:: Journal Volume: 21; Journal Issue: 4; Journal ID: ISSN 1359-6535

Publisher:: International Medical Press

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; Biological Science; danoprevir; mericitabine; modeling HCV therapy

Citation Formats


                    Canini, Laetitia, Guedj, Jeremie, Chatterjee, Anushree, Lemenuel-Diot, Annabelle, Smith, Patrick F., and Perelson, Alan S. Modelling the interaction between danoprevir and mericitabine in the treatment of chronic HCV infection.  United States: N. p., 2015. 
Web.  doi:10.3851/IMP3006.

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                    Canini, Laetitia, Guedj, Jeremie, Chatterjee, Anushree, Lemenuel-Diot, Annabelle, Smith, Patrick F., & Perelson, Alan S. Modelling the interaction between danoprevir and mericitabine in the treatment of chronic HCV infection.  United States.  https://doi.org/10.3851/IMP3006

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                    Canini, Laetitia, Guedj, Jeremie, Chatterjee, Anushree, Lemenuel-Diot, Annabelle, Smith, Patrick F., and Perelson, Alan S. Thu .  
"Modelling the interaction between danoprevir and mericitabine in the treatment of chronic HCV infection".  United States.  https://doi.org/10.3851/IMP3006.  https://www.osti.gov/servlets/purl/1324566.

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@article{osti_1324566,

  title        = {Modelling the interaction between danoprevir and mericitabine in the treatment of chronic HCV infection},

  author       = {Canini, Laetitia and Guedj, Jeremie and Chatterjee, Anushree and Lemenuel-Diot, Annabelle and Smith, Patrick F. and Perelson, Alan S.},

  abstractNote = {In this study, modelling HCV RNA decline kinetics under therapy has proven useful for characterizing treatment effectiveness. Here we model HCV viral kinetics (VK) in 72 patients given a combination of danoprevir, a protease inhibitor, and mericitabine, a nucleoside polymerase inhibitor, for 14 days in the INFORM-1 trial. A biphasic VK model with time-varying danoprevir and mericitabine effectiveness and Bliss independence for characterizing the interaction between both drugs provided the best fit to the VK data. As a result, the average final antiviral effectiveness of the drug combination varied between 0.998 for 100 mg three times daily of danoprevir and 500 mg twice daily of mericitabine and 0.9998 for 600 mg twice daily of danoprevir and 1,000 mg twice daily of mericitabine. Using the individual parameters estimated from the VK data collected over 2 weeks, we were not able to reproduce the low sustained virological response rates obtained in a more recent study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir for 24 weeks. In conclusion, this suggests that drug-resistant viruses emerge after 2 weeks of treatment and that longer studies are necessary to provide accurate predictions of longer treatment outcomes.},

  doi          = {10.3851/IMP3006},

  journal      = {Antiviral Therapy},

  number       = 4,

  volume       = 21,

  place        = {United States},

  year         = {Thu Jan 01 00:00:00 EST 2015},

  month        = {Thu Jan 01 00:00:00 EST 2015}

}

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