Pharmacokinetics and Pharmacodynamics of Peginterferon and Ribavirin: Implications for Clinical Efficacy in the Treatment of Chronic Hepatitis C

The pharmacokinetics and pharmacodynamics of standard interferon alfa-2a and interferon alfa-2b are substantially altered by pegylation. The size, geometry, and site of attachment of the PEG moiety affect the pharmacokinetics and pharmacodynamics as evidenced by the different absorption, volume of distribution, and clearance of the linear 12-kDa peginterferon alfa-2b and the branched 40-kDa peginterferon alfa-2a. Despite these differences, the clinical efficacy, safety, and tolerability of the 2 peginterferons are similar. However, evidence exists that peginterferon alfa-2 plus ribavirin is associated with small but significantly higher sustained virological response rates compared with peginterferon alfa-2b. This article discusses the pharmacokinetics and pharmacodynamics of the 2 peginterferons and their combination with ribavirin.

More than 3.2 million people in the United States and more than 200 million people worldwide are chronically infected with hepatitis C virus (HCV) and are at risk for the development of cirrhosis, decompensated liver disease, and hepatocellular carcinoma. The efficacy of therapy for chronic hepatitis C has improved from 10% to 20% with regimens using standard interferon-alfa monotherapy to 54% to 56% with regimens using peginterferon in combination with ribavirin. Thus, the current standard of treatment of chronic hepatitis C is the combination of a peginterferon with ribavirin administered for 24 or 48 weeks, depending on the HCV genotype. Two pegylated interferons are approved for the treatment of chronic hepatitis C: peginterferon alfa-2a and peginterferon alfa-2b. These compounds differ in size and the type of pegylation, resulting in different pharmacokinetics and pharmacodynamics. This article focuses on how the different properties of these compounds affect their in vivo performance and clinical efficacy.

Formulation of peginterferon alfa-2a and peginterferon alfa-2b

Pegylation is the process of covalent attachment of polyethylene glycol (PEG) polymer chains to another molecule, normally a drug or therapeutic protein. In general, pegylation results in improved pharmacokinetic and pharmacodynamic properties, increased drug stability, overall half-life and changes in tissue distribution pattern and elimination pathways. Molecular weight, configuration (linear or branched), and means of attachment of the PEG moiety are the primary contributors to the physicochemical properties of the PEG-peptide conjugate. Attachment of PEG at multiple sites can lead to steric interference between the compound and its receptor, which reduces the biologic activity of the conjugate. Pegylated interferon alfa-2a consists of a 40-kDa branched PEG moiety covalently attached to an interferon alfa-2a molecule. Pegylated interferon alfa-2b consists of a 12-kDa linear PEG molecule covalently attached to an interferon alfa-2b molecule. The branched PEG formulation has many advantages compared with the linear one. Although the 2 PEG molecules are of the same molecular mass, the branched PEG molecule acts as if it were much larger than the corresponding linear molecule. In addition, the branched-chain PEG conjugates have greater thermal and pH stability, are more resistant to proteolytic degradation, and are less antigenic because of the shielding of the attached polypeptide from the immune system. Key differences in the formulation of peginterferon alfa-2a and peginterferon alfa-2b are summarized in Table 1 .

Table 1

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