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Impact of Low-Dose Ritonavir on Danoprevir Pharmacokinetics

Results of Computer-Based Simulations and a Clinical Drug-Drug Interaction Study

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Abstract

Background and Objective

Danoprevir, a potent, selective inhibitor of the hepatitis C virus (HCV) NS3/4A protease, is metabolized by cytochrome P450 (CYP) Clinical studies in HCV patients have shown a potential need for a high danoprevir daily dose and/or dosing frequency. Ritonavir, an HIV-1 protease inhibitor (PI) and potent CYP3 A inhibitor, is used as a pharmacokinetic enhancer at subtherapeutic doses in combination with other HIV PIs. Coadministering danoprevir with ritonavir as a pharmacokinetic enhancer could allow reduced danoprevir doses and/or dosing frequency. Here we evaluate the impact of ritonavir on danoprevir pharmacokinetics.

Methods

The effects of low-dose ritonavir on danoprevir pharmacokinetics were simulated using Simcyp, a population-based simulator. Following results from this drug-drug interaction (DDI) model, a crossover study was performed in healthy volunteers to investigate the effects of acute and repeat dosing of low-dose ritonavir on danoprevir single-dose pharmacokinetics. Volunteers received a single oral dose of danoprevir 100 mg in a fixed sequence as follows: alone, and on the first day and the last day of 10-day dosing with ritonavir 100 mg every 12 hours.

Results

The initial DDI model predicted that following multiple dosing of ritonavir 100 mg every 12 hours for 10 days, the danoprevir area under the plasma concentration-time curve (AUC) from time zero to 24 hours and maximum plasma drug concentration (Cmax) would increase by about 3.9- and 3.2-fold, respectively. The clinical results at day 10 of ritonavir dosing showed that the plasma drug concentration at 12 hours postdose, AUC from time zero to infinity and Cmax of danoprevir increased by approximately 42-fold, 5.5-fold and 3.2-fold, respectively, compared with danoprevir alone. The DDI model was refined with the clinical data and sensitivity analyses were performed to better understand factors impacting the ritonavir-danoprevir interaction.

Conclusion

DDI model simulations predicted that danoprevir exposures could be successfully enhanced with ritonavir coadministration, and that a clinical study confirming this result was warranted. The clinical results demonstrate that low-dose ritonavir enhances the pharmacokinetic profile of low-dose danoprevir such that overall danoprevir exposures can be reduced while sustaining danoprevir trough concentrations.

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Acknowledgements

All authors were employees at Hoffmann-La Roche Inc. at the time this work was completed. Micaela Reddy, Jennifer Fretland and Patrick Smith are current employees at Hoffmann-La Roche Inc. Yuan Chen, Joshua Haznedar and Steven Blotner are current employees at Roche/Genentech. Joshua Haznedar owns stock in Roche. All authors have contributed to the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript. This study was supported by Hoffmann-La Roche, Basel, Switzerland. Support for third-party writing assistance for this manuscript was provided by Hoffmann-La Roche. The authors thank Drs Karin Jorga, Thierry Lave and Li Yu for providing valuable insight during the preparation of this manuscript. Additionally, we thank Dr Petra Goelzer for sharing her knowledge of the project.

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Authors and Affiliations

  1. Hoffmann-La Roche Inc., 340 Kingsland St, Nutley, New Jersey, NJ 07110-1199, USA

    Micaela B. Reddy, Jennifer Fretland, Steven Blotner & Patrick Smith

  2. Genentech Inc., South San Francisco, California, USA

    Yuan Chen & Joshua Ö. Haznedar

  3. Hoffmann-La Roche Inc., Palo Alto, California, USA

    Jonathan Q. Tran

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  1. Micaela B. Reddy
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Correspondence to Micaela B. Reddy.

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Reddy, M.B., Chen, Y., Haznedar, J.Ö. et al. Impact of Low-Dose Ritonavir on Danoprevir Pharmacokinetics. Clin Pharmacokinet 51, 457–465 (2012). https://doi.org/10.2165/11599700-000000000-00000

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