Clinical Pharmacokinetics of Interferons

Abstract

Interferons are a family of proteins shown to be effective in the treatment of viral (condylomata, acuminata) and neoplastic (hairy cell leukaemia and AIDS-related Kaposi's sarcoma) diseases. To date, the clinical utility of the interferons has been hampered by an incomplete understanding of their mechanism of action. However, there is supporting evidence that the route of administration, i.e. the pharmacokinetic behaviour, is an important treatment variable. The pharmacokinetics of interferons have been fairly well described. The decline in serum concentrations of interferon is rapid after intravenous administration. The volume of distribution approximates 20 to 60% of bodyweight. Work in animals suggests that the catabolism of interferons falls within the natural handling of proteins. Clearance values vary (4.8 to 48 L/h) across the family of interferons and probably reflect the natural internal digestion and turnover of these proteins. Terminal elimination half-lives range from 4 to 16 hours, 1 to 2 hours and 25 to 35 minutes for alpha, beta and gamma, respectively. Intramuscular and subcutaneous administration of interferons alpha and beta results in protracted but fairly good absorption: greater than 80% for interferon-alpha and 30 to 70% for interferon-gamma. Interferon therapy is associated with adverse events which are usually mild and reversible. Temporal relationships exist between the degree and duration of adverse effects and the route of administration. Attempts to relate inducible biochemical markers, such as 2',5'-oligoadenylate synthetase activity, to dose or concentration have met with some success although alterations in these markers have not been shown to relate to clinical response.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and safety of pegylated (40-kd) interferon α-2a compared with interferon α-2a in noncirrhotic patients with chronic hepatitis C

“…1,2 IFN has a half-life of approximately 8 hours, and, consequently, a 3-times-weekly dosing schedule may be insufficient to maintain adequate serum concentrations. 4 Pegylated interferon ␣-2a (PEG[40kd] IFN ␣-2a) was developed in an attempt to improve the pharmacological profile of IFN ␣-2a. Covalent attachment of a branched 40-kd polyethylene glycol moiety to IFN ␣-2a results in more sustained absorption (time to peak plasma concentration increased Ͼ7-fold), reduced clearance (10-fold), and a smaller volume of distribution (4-fold), thereby permitting once-weekly dosing.…”

Side effects of ? interferon in chronic hepatitis C

“…Granulocytes, platelets, and red below the limit of detection by 16 hours. 1 The elimination blood cell counts decrease during treatment, but the decreases half-life of interferon after both subcutaneous and intramusare usually mild, although they can be dose limiting if cell cular injections is 2 to 3 hours, and clearance from the syscounts are low initially. Interferon has important immuno-temic circulation is primarily by renal catabolism.…”

Adenovirus delivery provides extended interferon-α exposure and augments treatment of metastatic carcinoma

“…Unmodified interferon-a protein has a short serum half-life characterized by a spike in serum concentration followed by rapid clearance. 31,32 Here, we utilize rAd based vectors as a means to deliver IFNa2a1 and to avoid wide fluctuations in the protein levels associated with protein therapy. Interferon is expressed as secreted protein in rAd-transduced cells, thus providing both autocrine and paracrine signaling to receptor positive cells.…”