• 17
    Jun
  • Peginterferon alfa-2a

PeginterferonIt is estimated that between 2.7 million and 4.0 million people in the U.S. have chronic hepatitis C virus (HCV) infection. Since the early 1980s, the use of injected drugs has been the greatest risk factor for HCV infection. Drug use currently accounts for 60% of cases of newly acquired infection, and 20% to 50% of these cases involve patients with chronic infection.

It has been projected that the mortality rate and health care costs from complications of chronic hepatitis C and cirrhosis, such as hepatocellular carcinoma and liver failure, will increase dramatically over the next two decades. As a result, it is generally agreed that more effective interferon-based treatments need to be developed. In October 2002, peginterferon alfa-2a (Pegasys®, Roche) was approved for the treatment of adults with chronic hepatitis C who have compensated liver disease and who have not previously been treated with alpha inter-ferons, including patients with compensated cirrhosis.
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PHARMACOLOGY

Pegasys® is a covalent conjugate of recombinant alfa-2a interferon with a single branched bis-monomethoxy polyethylene glycol (PEG) chain. The PEG moiety is linked at a single site to the interferon alfa moiety via a stable amide bond to lysine.

Interferons bind to specific receptors on the cell surface, initiating intracellular signaling via a complex cascade of protein-protein interactions that lead to rapid activation of gene transcription. The inhibition of viral replication in infected cells, the inhibition of cell proliferation, and immunomodulation are some of the biological effects that are regulated by interferon-stimulated genes. Pegasys® stimulates the production of effector proteins, such as serum neop-terin and 2′,5′-oligoadenylate synthetase; it raises body temperature, and it causes reversible decreases in leukocyte and platelet counts.

PHARMACOKINETICS

Maximal serum concentrations (Cmax) occur between 72 and 96 hours after a dose of peginterferon alfa-2a, 180 mcg, and are sustained for up to 168 hours. The Cmax and area-under-the-curve (AUC) measurements of this drug increase in a dose-related manner. The mean trough concentrations from week 48 (16 ng/ml; range, 4-28) are approximately two-fold higher than those from week one (8 ng/ml; range, 0-15). Steady-state serum levels are reached within five to eight weeks of once-weekly dosing. The mean systemic clearance in healthy subjects who have received Pegasys® was 94 ml/hour, which is approximately 100-fold lower than that for interferon alfa-2a.
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Administration of peginterferon alfa-2a yields similar pharmacokinetics in healthy male and female patients. In patients older than 62 years taking 180 mcg of the drug, the AUC concentration was increased from 1,295 to 1,663 ng x hours/ml. Peak concentrations, however, were similar in those patients who were older than age 62 (9 ng/ml) and those who were younger than age 62 years (10 ng/ml).

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