Boceprevir, an NS3 Protease Inhibitor of HCV

Berman, Kenneth; Kwo, Paul Y.

doi:10.1016/j.cld.2009.05.008

Cited by 56 publications

(38 citation statements)

References 29 publications

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“…In patients with genotype 1 HCV infection, sustained viral response rates remain suboptimal, with less than half of genotype 1-infected individuals going on to achieve sustained viral response. This response has led to a shift in the investigational focus for treatment of HCV toward specifically targeted antiviral therapy for HCV agents (Berman and Kwo, 2009). Structural determination of key replication enzymes such as the HCV protease NS3/NS4 (nonstructural protein) has enabled the design and synthesis of new HCVspecific drugs.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Ghosal¹,

Yuan²,

Tong³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Boceprevir (SCH 503034), a protease inhibitor, is under clinical development for the treatment of human hepatitis C virus infections. In human liver microsomes, formation of oxidative metabolites after incubations with [ 14 C]boceprevir was catalyzed by CYP3A4 and CYP3A5. In addition, the highest turnover was observed in recombinant CYP3A4 and CYP3A5. After a single radiolabeled dose to human, boceprevir was subjected to two distinct pathways, namely cytochrome P450-mediated oxidation and ketone reduction. Therefore, attempts were made to identify the enzymes responsible for the formation of carbonyl-reduced metabolites. Human liver S9 and cytosol converted ϳ28 and ϳ68% of boceprevir to M28, respectively, in the presence of an NADPHgenerating system. Screening of boceprevir with recombinant human aldo-keto reductases (AKRs) revealed that AKR1C2 and AKR1C3 exhibited catalytic activity with respect to the formation of M؉2 metabolites (M28 and M31). The formation of M28 was inhibited by 100

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Section: Introductionmentioning

confidence: 99%

Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Ghosal¹,

Yuan²,

Tong³

et al. 2010

Drug Metab Dispos

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“…Furthermore, we calculated in a two-way sensitivity analysis the cost-effectiveness of more effective treatment strategies with addition of further drugs, such as hematopoietic growth factors or direct-acting antivirals, to the Peg-IFN/ RBV regimen [34][35][36][37]. In patients infected with HCV genotype 1, additional €10 774 can be spent per 10% SVR gain without changing cost-effectiveness.…”

Section: Discussionmentioning

confidence: 99%

Cost-effectiveness analysis of antiviral treatment in liver transplant recipients with HCV infection

et al. 2013

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SummaryWithin 5-10 years, 20-40% of hepatitis C virus (HCV)-infected liver transplant recipients can be expected to develop cirrhosis. Here, cost-effectiveness of antiviral therapy was assessed. A Markov model was developed to simulate disease progression and calculate outcome and costs of treatment. In the baseline analysis, Peg-IFN/RBV treatment prevented organ loss/death, gained quality-adjusted lifeyears (QALYs) and undercut the limit of cost-effectiveness of €50 000/QALY with an incremental cost-effectiveness ratio of approximately €40 400/QALY and €21 000/QALY for HCV genotype 1 and 2/3 patients, respectively. Furthermore, sensitivity analysis testing modified model parameters according to extreme data described in the literature confirmed cost-effectiveness for a lower or higher rate of fibrosis progression, increased non-HCV-related mortality, lower limits of utilities, a time horizon of 30 years, and additional costs in the year of death. On the other hand, cost-effectiveness was lost for patients with genotype 1 in case of doubled antiviral or life-time costs or an increased discount rate of 7%. New treatment strategies for HCV genotype 1 infected patients remained on the same level cost-effective, if additional costs did not exceed €10 774 per 10% sustained virologic response gain. We conclude that Peg-IFN/RBV treatment is cost-effective post transplant. This may support treatment decision in individual cases.

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“…The first 2 DAAs to emerge are the protease inhibitors boceprevir and telaprevir. 23,24 Telaprevir is an orally bioavailable NS3 protease inhibitor that belongs to the alfaketoamides and binds to the enzyme covalently but reversibly. Two landmark phase 2 studies, PROVE-1 (conducted in the United States) and PROVE-2 (conducted in Europe), showed an excellent response to therapy in treatment-naive patients infected with genotype 1.…”

Section: Ns3 Protease Inhibitorsmentioning

confidence: 99%

“…This strategy may also have the potential to define a patient's interferon responsiveness before adding the DAA. 23,24 The phase II study (SPRINT-1) was conducted in treatment-naive patients infected with HCV genotype 1. Patients who received boceprevir had higher SVR rates compared with the control, and after 48 weeks of treatment, SVR rates of 75% were noted.…”

Section: Ns3 Protease Inhibitorsmentioning

confidence: 99%

Management of the Treatment-Experienced Patient Infected with Hepatitis C Virus Genotype 1: Options and Considerations

Khalid

Bacon

2011

Clinics in Liver Disease

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Boceprevir, an NS3 Protease Inhibitor of HCV

Cited by 56 publications

References 29 publications

Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Cost-effectiveness analysis of antiviral treatment in liver transplant recipients with HCV infection

Management of the Treatment-Experienced Patient Infected with Hepatitis C Virus Genotype 1: Options and Considerations

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