Impact of low-dose ritonavir on danoprevir pharmacokinetics: results of computer-based simulations and a clinical drug-drug interaction study.
ABSTRACT Danoprevir, a potent, selective inhibitor of the hepatitis C virus (HCV) NS3/4A protease, is metabolized by cytochrome P450 (CYP) 3A. 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 CYP3A 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.
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.
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 (C(max)) 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 C(max) 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.
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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ABSTRACT: Danoprevir is a macrocyclic hepatitis C virus protease inhibitor in clinical development in combination with ritonavir. This study investigated whether ritonavir-boosted danoprevir (DNVr) affects cardiac repolarization, as measured by study-specific corrected QT (QTcS) interval. This was a single-center, single-dose, randomized, double-blind, double-dummy, four-way crossover study. Healthy subjects received a single dose of each treatment (therapeutic-dose DNVr 100/100 mg; supratherapeutic-dose DNVr 400/100 mg; positive control [moxifloxacin 400 mg]; placebo) by randomized sequence, at least 7 days apart. Triplicate readings by continuous Holter 12-lead digital electrocardiogram (Mortara Instruments, Inc., Milwaukee, WI) were obtained during day 1 and 24 h postdose. There was no clinically relevant increase in QTcS interval with DNVr compared with placebo in 52 subjects. The upper one-sided 95% confidence interval for placebo-subtracted change from baseline QTcS wasDrug Development Research 08/2013; 74(5). DOI:10.1002/ddr.21080 · 0.73 Impact Factor
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ABSTRACT: Drug development for chronic hepatitis C is progressing at a furious rate; after more than 10 years spent at optimizing Pegylated Interferon and Ribavirin regimens, the ability to design drugs targeting key steps of the HCV life cycle has allowed the development of several directly acting antivirals (DAA). The NS3/4A Protease inhibitors Telaprevir and Boceprevir, have been a major breakthrough for patients and clinicians as they finally allowed patients with HCV genotype 1 to achieve high SVR rates, that top the 80% mark in some highly responsive subgroups (1-4). Unfortunately, both drugs did not solve all our problems due to a significant pill burden, clinically relevant drug-drug interactions and most importantly the fact that their efficacy is heavily relying on the activity of the PegIFN/Rbv backbone. This article is protected by copyright. All rights reserved.Liver international: official journal of the International Association for the Study of the Liver 03/2014; 34(7). DOI:10.1111/liv.12543 · 4.41 Impact Factor
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ABSTRACT: Background & Aims: Danoprevir (DNV) is a hepatitis C virus (HCV) protease inhibitor that achieves high sustained virologic response (SVR) rates in combination with peginterferon alfa-2a/ribavirin in treatment-naive HCV genotype (G)1-infected patients. This study explored the efficacy and safety of ritonavir-boosted DNV (DNVr) plus peginterferon alfa-2a/ribavirin in G1 prior peginterferon/ribavirin null responders.Methods: Null responders (<2-log10 reduction in HCV RNA at week 12) were given open-label DNVr 100/100 mg q12h + peginterferon alfa-2a/ribavirin for 12 weeks. All patients achieving an early virologic response (EVR; ≥2-log10 decrease in HCV RNA by week 12) continued treatment with peginterferon alfa-2a/ribavirin; those without an EVR discontinued all study drugs.Results: Twenty-four prior null responders were enrolled; 16 patients (67%) were infected with HCV G1b, and 8 (33%) with G1a. 96% of patients had an IL28B non-CC genotype. An SVR24 was achieved in 67% of patients, with a higher rate in G1b-infected (88%) vs. G1a-infected (25%) patients. Resistance-related breakthrough occurred in 4/8 G1a and 1/16 G1b patients through the DNV resistance-associated variant (RAV) NS3 R155K. NS3 R155K was also detected in 2/2 G1a patients who relapsed. Treatment was well tolerated. Two patients withdrew prematurely from study medications due to adverse events. Two serious adverse events were reported; both occurred after completion of DNVr therapy and were considered unrelated to treatment. No Grade 3/4 ALT elevations were observed.Conclusions: DNVr plus peginterferon alfa-2a/ribavirin demonstrated high SVR24 rates in HCV G1b prior null responders and was well tolerated.Antimicrobial Agents and Chemotherapy 12/2013; DOI:10.1128/AAC.01515-13 · 4.45 Impact Factor