Interferon alfa-2a clinical pharmacology

Interferon alfa-2a
PEGASYS® FDA Package Insert
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Clinical Pharmacology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Clinical Pharmacology

The mechanism by which Interferon alfa-2a, recombinant, or any other interferon, exerts antitumor or antiviral activity is not clearly understood. However, it is believed that direct antiproliferative action against tumor cells, inhibition of virus replication and modulation of the host immune response play important roles in antitumor and antiviral activity.

The biological activities of Interferon alfa-2a, recombinant are species-restricted, i.e., they are expressed in a very limited number of species other than humans. As a consequence, preclinical evaluation of Interferon alfa-2a, recombinant has involved in vitro experiments with human cells and some in vivo experiments.1 Using human cells in culture, Interferon alfa-2a, recombinant has been shown to have antiproliferative and immunomodulatory activities that are very similar to those of the mixture of interferon alfa subtypes produced by human leukocytes. In vivo, Interferon alfa-2a, recombinant has been shown to inhibit the growth of several human tumors growing in immunocompromised (nude) mice. Because of its species-restricted activity, it has not been possible to demonstrate antitumor activity in immunologically intact syngeneic tumor model systems, where effects on the host immune system would be observable. However, such antitumor activity has been repeatedly demonstrated with, for example, mouse interferon-alfa in transplantable mouse tumor systems. The clinical significance of these findings is unknown.

The metabolism of Interferon alfa-2a, recombinant is consistent with that of alpha-interferons in general. Alpha-interferons are totally filtered through the glomeruli and undergo rapid proteolytic degradation during tubular reabsorption, rendering a negligible reappearance of intact alfa interferon in the systemic circulation. Small amounts of radiolabeled Interferon alfa-2a, recombinant appear in the urine of isolated rat kidneys, suggesting near complete reabsorption of Interferon alfa-2a, recombinant catabolites. Liver metabolism and subsequent biliary excretion are considered minor pathways of elimination for alfa interferons.

The serum concentrations of Interferon alfa-2a, recombinant reflected a large intersubject variation in both healthy volunteers and patients with disseminated cancer.

In healthy people, Interferon alfa-2a, recombinant exhibited an elimination half-life of 3.7 to 8.5 hours (mean 5.1 hours), volume of distribution at steady-state of 0.223 to 0.748 L/kg (mean 0.400 L/kg) and a total body clearance of 2.14 to 3.62 mL/min/kg (mean 2.79 mL/min/kg) after a 36 MIU (2.2×108pg) intravenous infusion. After intramuscular and subcutaneous administrations of 36 MIU, peak serum concentrations ranged from 1500 to 2580 pg/mL (mean 2020 pg/mL) at a mean time to peak of 3.8 hours and from 1250 to 2320 pg/mL (mean 1730 pg/mL) at a mean time to peak of 7.3 hours, respectively. The apparent fraction of the dose absorbed after intramuscular injection was greater than 80%.

The pharmacokinetics of Interferon alfa-2a, recombinant after single intramuscular doses to patients with disseminated cancer were similar to those found in healthy volunteers. Dose proportional increases in serum concentrations were observed after single doses up to 198 MIU. There were no changes in the distribution or elimination of Interferon alfa-2a, recombinant during twice daily (0.5 to 36 MIU), once daily (1 to 54 MIU), or three times weekly (1 to 136 MIU) dosing regimens up to 28 days of dosing. Multiple intramuscular doses of Interferon alfa-2a, recombinant resulted in an accumulation of two to four times the single dose serum concentrations. There is no pharmacokinetic information in patients with chronic hepatitis C, hairy cell leukemia, and chronic myelogenous leukemia.

Serum neutralizing activity, determined by a highly sensitive enzyme immunoassay, and a neutralization bioassay, was detected in approximately 25% of all patients who received Roferon-A.2 Antibodies to human leukocyte interferon may occur spontaneously in certain clinical conditions (cancer, systemic lupus erythematosus, herpes zoster) in patients who have never received exogenous interferon.3 The significance of the appearance of serum neutralizing activity is not known.

References

Adapted from the FDA Package Insert.