Clinical Pharmacology Profile of Boceprevir, a Hepatitis C Virus NS3 Protease Inhibitor: Focus on Drug–Drug Interactions

Abstract

Boceprevir is a potent, orally administered ketoamide inhibitor that targets the active site of the hepatitis C virus (HCV) non-structural (NS) 3 protease. The addition of boceprevir to peginterferon plus ribavirin resulted in higher rates of sustained virologic response (SVR) than for peginterferon plus ribavirin alone in phase III studies in both previously treated and untreated patients with HCV infection. Because boceprevir is metabolized by metabolic routes common to many other drugs, and is an inhibitor of cytochrome P450 (CYP) 3A4/5, there is a high potential for drug-drug interactions when boceprevir is administered with other therapies, particularly when treating patients with chronic HCV infection who are often receiving other medications concomitantly. Boceprevir is no longer widely used in the US or EU due to the introduction of second-generation treatments for HCV infection. However, in many other geographic regions, first-generation protease inhibitors such as boceprevir continue to form an important treatment option for patients with HCV infection. This review summarizes the interactions between boceprevir and other therapeutic agents commonly used in this patient population, indicating dose adjustment requirements where needed. Most drug interactions do not affect boceprevir plasma concentrations to a clinically meaningful extent, and thus efficacy is likely to be maintained when boceprevir is coadministered with the majority of other therapeutics. Overall, the drug-drug interaction profile of boceprevir suggests that this agent is suitable for use in a wide range of HCV-infected patients receiving concomitant therapies.

Mechanisms and Predictions of Drug-Drug Interactions of the Hepatitis C Virus Three Direct-Acting Antiviral Regimen: Paritaprevir/Ritonavir, Ombitasvir, and Dasabuvir

“…Successful HCV therapies may require a combination of DAAs similar to HIV regimens; in some cases, the use of pharmacokinetic (PK) enhancers such as ritonavir may be needed. Approved HCV protease inhibitors (e.g., telaprevir, boseprevir, and simeprevir) and polymerase inhibitors (e.g., prodrug sofosbuvir) are substrates and inhibitors of drug-metabolizing enzymes and transporters, which are regularly involved in DDIs (Maasoumy et al, 2013;Khalilieh et al, 2015;Kirby et al, 2015). AbbVie's three direct-acting antiviral (3D) regimen is an all-oral interferon-free combination of the protease inhibitor paritaprevir (identified by AbbVie and Enanta) coformulated with ritonavir as a systemic PK enhancer and the Nonstructural protein 5A (NS5A) inhibitor ombitasvir, plus the non-nucleoside polymerase inhibitor dasabuvir with and without ribavirin (Feld et al, 2014).…”

3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials

“…Boceprevir is used as a protease inhibitor for the hepatitis C virus (HCV) [90] by containing an α-ketoamide that forms a covalent bond with the serine active site in the 3CLpro protein. It proved to be an effective drug in virtual screening and in vitro assays.…”

3-Chymotrypsin-like Protease (3CLpro) of SARS-CoV-2: Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials

“…Boceprevir is used as a protease inhibitor for the hepatitis C virus (HCV) [ 101 ] by containing an α-ketoamide that forms a covalent bond with the serine active site in the 3CLpro protein. It proved to be an effective drug in virtual screening and in vitro assays.…”