Characterization of vaniprevir, a hepatitis C virus NS3/4A protease inhibitor, in patients with HCV genotype 1 infection: Safety, antiviral activity, resistance, and pharmacokinetics

Lawitz, Eric; Sulkowski, Mark S.; Jacobson, Ira M.; Kraft, Walter K.; Maliakkal, Benedict; Al-Ibrahim, Mohamed S.; Gordon, Stuart C.; Kwo, Paul Y.; Rockstroh, Juergen; Panorchan, Paul; Miller, Michelle; Caro, Luzelena; Barnard, Richard; Hwang, Peggy; Gress, Jacqueline; Quirk, Erin; Mobashery, Niloufar

doi:10.1016/j.antiviral.2013.05.015

Cited by 30 publications

(20 citation statements)

References 13 publications

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“…The trends observed in the present PK data in healthy subjects are generally similar to those reported previously in patients with HCV infection, both when administered as a monotherapy and when used in combination with peginterferon and ribavirin . When administered as monotherapy in patients with HCV infection, greater‐than‐dose‐proportional increases in vaniprevir exposure were reported, with higher doses being associated with improved antiviral efficacy . Lawitz et al .…”

Section: Discussionsupporting

confidence: 88%

“…10,19 Vaniprevir has low-to-moderate bioavailability; therefore, minor physiologic changes (e.g., body weight and liver size) affecting first-pass processes (e.g., hepatic uptake) may be contributing to the moderate-to-high vaniprevir PK variability. 20 The trends observed in the present PK data in healthy subjects are generally similar to those reported previously in patients with HCV infection, both when administered as a monotherapy 14 and when used in combination with peginterferon and ribavirin. 15 When administered as monotherapy in AUC, area under the curve; C 12h , plasma concentration at 12 h postdose; C 24h , plasma concentration at 24 h postdose; C max , maximum concentration; t max , time taken to reach C max occurred; t ½ , elimination half-life.…”

Section: Discussionsupporting

confidence: 88%

“…to 500 mg b.i.d.) decrease in HCV RNA of 1.8–4.6 log 10 IU/mL following 1 week of monotherapy . Subsequent clinical trials have shown the combination of vaniprevir plus peginterferon and ribavirin to be safe and effective for treatment‐naive and treatment‐experienced patients with HCV GT1 infection .…”

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confidence: 99%

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Single‐Dose and Multiple‐Dose Pharmacokinetics of Vaniprevir in Healthy Men

Caro

Hoon

Depré

et al. 2017

Clinical Translational Sci

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Vaniprevir is an inhibitor of the hepatitis C virus (HCV) NS3/4A protease. The aim of these double-blind, placebo-controlled phase I studies was to evaluate the safety and pharmacokinetics of vaniprevir in healthy male volunteers. The primary objective for both studies was the safety and tolerability of vaniprevir. Single-dose and steady-state pharmacokinetics were also assessed. In both studies, there was no apparent relationship between the frequency or intensity of adverse events and vaniprevir dose. At single doses >20 mg, the plasma area under the curve (AUC) 0-Ý and maximum concentration (C max ) increased in a greater-thandose-proportional manner. The geometric mean ratios (GMRs; fed/fasted) were 1.22 and 0.79 for AUC 0-Ý and C max , respectively. Following multiple doses, GMR accumulations for AUC 0-12h and C max (day 14/day 1) ranged from 1.53 to 1.90 and from 1.41 to 1.92, respectively. These data support the use of vaniprevir with peginterferon and ribavirin in patients with HCV infection.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 88%

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Single‐Dose and Multiple‐Dose Pharmacokinetics of Vaniprevir in Healthy Men

Caro

Hoon

Depré

et al. 2017

Clinical Translational Sci

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“…The NS3 amino acid substitutions most commonly observed in genotype 1a–infected patients who did not achieve SVR were R155K and D168T/V/Y. The NS3 amino acid substitutions most commonly observed in genotype 1b–infected patients who did not achieve SVR were D168H/T/V …”

Section: Ns3/4a Protease Inhibitorsmentioning

confidence: 99%

Hepatitis C virus drug resistance–associated substitutions: State of the art summary

et al. 2015

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Hepatitis C virus (HCV) drug development has resulted in treatment regimens composed of interferon‐free, all‐oral combinations of direct‐acting antivirals. While the new regimens are potent and highly efficacious, the full clinical impact of HCV drug resistance, its implications for retreatment, and the potential role of baseline resistance testing remain critical research and clinical questions. In this report, we discuss the viral proteins targeted by HCV direct‐acting antivirals and summarize clinically relevant resistance data for compounds that have been approved or are currently in phase 3 clinical trials. Conclusion: This report provides a comprehensive, systematic review of all resistance information available from sponsors’ trials as a tool to inform the HCV drug development field. (Hepatology 2015;62:1623–1632)

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“…The most commonly reported drug-related adverse events in early phase clinical development were diarrhea, nausea and vomiting [25]. In phase 2 studies in combination with P/R, most gastrointestinal adverse events were mild to moderate in intensity [23].…”

Section: Vaniprevir (Formerly Mk-7009)mentioning

confidence: 99%