Peginterferon-α-2a (40 kD) Plus Ribavirin

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Abstract
Peginterferon-α-2a (40 kD) [PEGASYS®] is a conjugate of recombinant interferon-α-2a and a 40 kD branched polyethylene glycol (PEG) moiety that is highly active against hepatitis C virus (HCV). Ribavirin (COPEGUS®) is a synthetic nucleoside analogue that acts in synergy with the antiviral activity of peginterferon-α-2a (40 kD). The combination of subcutaneous peginterferon-α-2a (40 kD) once weekly plus oral ribavirin twice daily is widely approved for use in adult patients with chronic hepatitis C, including those with persistently ‘normal’ ALT activity or HIV-HCV co-infection, and is recommended as a first-line treatment option for patients with chronic hepatitis C and compensated liver disease. In randomized, phase III trials, the combination has consistently demonstrated good therapeutic efficacy (i.e. high sustained virological response [SVR] rates) and has been generally well tolerated in both treatment-naive and treatment-experienced patients with chronic hepatitis C, including those with compensated advanced liver disease. Several baseline and dynamic (on-treatment) predictors of SVR that can be used to guide and optimize therapy were also determined in these trials and in subsequent analyses. By utilizing these predictors, therapy with peginterferon-α-2a (40 kD) plus ribavirin can be individualized to achieve the optimal balance between efficacy and tolerability, further increasing the usefulness of this drug combination. Thus, peginterferon-α-2a (40 kD) plus ribavirin remains a valuable therapy in patients with chronic hepatitis C, as a first-line option in those with compensated liver disease and as a second-line therapy in those with advanced liver disease. Peginterferon-α-2a (40 kD) is a covalent conjugate of recombinant interferon-α-2a and a 40 kD single branched PEG moiety. Peginterferon-α-2a (40 kD) shows antiviral activity in vitro against HCV and clinically significant activity in patients with chronic hepatitis C. The anti-HCV activity of interferon-α-2a is augmented by pegylation. Ribavirin is a synthetic nucleoside analogue that shows activity in vitro against some RNA and DNA viruses. Although the exact mechanism is not known, ribavirin acts synergistically with peginterferon-α-2a (40 kD) in patients with chronic hepatitis C to improve SVR rates and reduce virological relapse after treatment cessation. In addition, the therapeutic efficacy of peginterferon-α-2a (40 kD) plus ribavirin is aided by the ability of both drugs to modulate and restore the impaired HCV-specific immune responses seen in patients with chronic HCV infection. The pharmacokinetic properties of peginterferon-α-2a (40 kD) are largely influenced by the presence of the PEG moiety. As a consequence of pegylation, the drug is absorbed slowly following subcutaneous injection, has distribution restricted to the blood and highly perfused organs, is protected from rapid enzymatic degradation in the liver and has a slow clearance rate. Following subcutaneous administration of peginterferon-α-2a (40 kD) 180 µg once weekly, serum drug concentrations are maintained throughout the dose administration interval, with a narrow peak-to-trough concentration ratio. Ribavirin is rapidly and extensively absorbed following oral administration. The absolute bioavailability of the drug is limited because of first-pass metabolism outside the liver, but can be improved with coadministration of a high-fat meal. Ribavirin is distributed widely in, and eliminated slowly from, the non-plasma compartments. The drug is mainly eliminated in the urine as metabolites or unchanged drug (5–15% of an administered dose). Combined administration of subcutaneous peginterferon-α-2a (40 kD) and oral ribavirin does not seem to alter the pharmacokinetic properties of either drug. In Treatment-Naive Patients: Subcutaneous peginterferon-α-2a (40 kD) 180 µg once weekly plus oral ribavirin 800 mg/day or 1000–1200 mg/day was previously shown to produce SVR (i.e. undetectable [In Routine Clinical Practice: In several open-label, multicentre, national studies reflecting a ‘real world’ setting, peginterferon-α-2a (40 kD) 180 µg once weekly plus ribavirin 800 or 1000 or 1200 mg/day achieved SVR rates consistent with those reported in pivotal phase III clinical trials in patients with chronic hepatitis C. The EVR at week 12 as a predictor of non-response was also confirmed in this setting. The combination of peginterferon-α-2a (40 kD) plus ribavirin was generally well tolerated in randomized, phase III trials in patients with chronic hepatitis C. Most patients experienced at least one adverse event, which were generally mild to moderate in severity. The most common clinical adverse events included headache, fatigue, myalgia and pyrexia, and the most frequent laboratory abnormalities were neutropenia and thrombocytopenia associated with peginterferon-α-2a (40 kD) [which resolved within a few weeks of treatment cessation] and haemolytic anaemia associated with ribavirin. Approximately one-third of patients receiving peginterferon-α-2a (40 kD) plus ribavirin regimens required dosage reduction to manage adverse events or haematological abnormalities, and 11% of patients required complete drug discontinuation. The most frequent of these adverse events were therapy-related psychiatric, dermatological, gastrointestinal and ‘flu-like’ adverse events or haematological abnormalities. As might be expected, a lower incidence of ribavirin dose modifications because of adverse events or laboratory abnormalities was observed in patients who received shorter treatment regimens. However, extending treatment from 48 to 72 weeks did not significantly increase the incidence or severity of adverse events.