Drug–drug interactions during antiviral therapy for chronic hepatitis C

Abstract

The emergence of direct-acting antiviral agents (DAAs) for HCV infection represents a major advance in treatment. The NS3 protease inhibitors, boceprevir and telaprevir, were the first DAAs to receive regulatory approval. When combined with PEG-IFN and ribavirin, these agents increase rates of sustained virologic response in HCV genotype 1 to ~70%. However, this treatment regimen is associated with several toxicities. In addition, both boceprevir and telaprevir are substrates for and inhibitors of the drug transporter P-glycoprotein and the cytochrome P450 enzyme 3A4 and are, therefore, prone to clinically relevant drug interactions. Several new DAAs for HCV are in late stages of clinical development and are likely to be approved in the near future. These include the protease inhibitors, simeprevir and faldaprevir, the NS5A inhibitor, daclatasvir, and the nucleotide polymerase inhibitor, sofosbuvir. Herein, we review the clinical pharmacology and drug interactions of boceprevir, telaprevir and these investigational DAAs. Although boceprevir and telaprevir are involved in many interactions, these interactions are manageable if health-care providers proactively identify and adjust treatments. Emerging DAAs seem to have a reduced potential for drug interactions, which will facilitate their use in the treatment of HCV.

Mechanisms Underlying Benign and Reversible Unconjugated Hyperbilirubinemia Observed with Faldaprevir Administration in Hepatitis C Virus Patients

“…Both asunaprevir and the protease inhibitor ABT-450 have been reported to be associated with bilirubin elevations (Poordad et al, 2013;Suzuki et al, 2013). These observations are consistent with the known inhibitory effect of asunaprevir and ABT-450 on OATP1B1/OATP1B3 (Kiser et al, 2013;Lawitz et al, 2012). …”

“…For example, simeprevir has been shown to inhibit OATP1B1 and MRP2, which may explain the mixed conjugated and unconjugated hyperbilirubinemia observed in HCV-infected patients during simeprevir treatment (Kiser et al, 2013). Both asunaprevir and the protease inhibitor ABT-450 have been reported to be associated with bilirubin elevations (Poordad et al, 2013;Suzuki et al, 2013).…”

Direct acting anti-hepatitis C virus drugs: Clinical pharmacology and future direction

“…Pharmacokinetic interactions are partially predictable based on the available data and can be limited or prevented by a dosage adjustment. [33,34] Direct acting antiviral-related pharmacodynamic drug interactions The co-administration of protease inhibitors with other drugs such as clarithromycin or moxifloxacin may alter the QT interval result in critical arrhythmia due to the prolongation of QT interval. So, the precautions for QT interval prolongation should be considered in patients who are initiating protease inhibitor therapy and are under medications with proarrhythmic potential.…”

“…Boceprevir and telaprevir, the first wave members of NS3/4A inhibitors, were reported to interact with azole antifungal, immunosuppressants. [34,44] Second generation are not yet approved and data about their interactions are limited. The newer DAA agents such as sofosbuvir (an HCV NS5B polymerase inhibitor) and ledipasvir (an HCV NS5A inhibitor), which are not or only marginally affected by CYP450 enzymes, are relatively less vulnerable to significant hepatic pharmacokinetic interactions.…”

Chronic hepatitis C: This and the new era of treatment

“…Boceprevir causes dysguesia and anaemia [43] . Several drug-drug interactions can occur, so the use of first-generation PIs has been significantly restricted [82] . …”