Pharmacology and pharmaceutics

Clinical pharmacology According to the product label, the most striking differences between interferon-gamma and other classes of interferon concern the immunomodulatory properties of this molecule. While gamma, alpha, and beta interferons share certain properties, interferon-gamma has potent phagocyte-activating effects not seen with other interferon preparations. These effects include the generation of toxic oxygen metabolites within phagocytes in vitro, which are capable of mediating the intracellular killing of selected microorganisms. To the extent that interferon-gamma is produced by antigen-stimulated T-lymphocytes and regulates the activity of immune cells, it is appropriate to characterize interferon-gamma as a lymphokine of the interleukin type. With respect to chronic granuloma-tous disease (an inherited disorder characterized by deficient phagocyte oxidative metabolism), clinical trials of the systemic administration of Actimmune provided evidence for a treatment-related enhance-

ment of phagocyte function including elevation of superoxide levels and improved killing of Staphylococcus aureus. In severe, malignant osteopetrosis (another inherited disorder characterized by an osteoclast defect leading to bone overgrowth and deficient phagocyte oxidative metabolism), a treatment-related enhancement of superoxide production by phagocytes was observed in situ. Interferon gamma-lb was also found to enhance osteoclast function in vitro.

Pharmacokinetics According to product label, interferon gamma-lb is rapidly cleared after intravenous administration (1.4liters/min) and slowly absorbed after intramuscular or subcutaneous injection. After intramuscular or subcutaneous injection, the apparent fraction of dose absorbed was greater than 90%. The mean elimination half-life after intravenous administration in healthy male subjects was 38 minutes.The mean elimination half-lives after intramuscular or subcutaneous dosing were 2.9 and 5.9 hours, respectively. Pharmacokinetic studies in patients with chronic granulomatous disease have not been performed.

Disposition No information available.

Drug interactions Interactions between Actimmune and other drugs have not been fully evaluated. Caution should be exercised when administering Actimmune in combination with other potentially myelosuppressive agents.

E. Therapeutic response A randomized, double-blind, placebo-controlled study of Actimmune in patients with chronic granulomatous disease was terminated early following demonstration of a highly statistically significant benefit of Actim-mune therapy compared to placebo with respect to time to serious infection, the primary end point of the investigation. A controlled, randomized study in patients with severe, malignant osteopetrosis com pared Actimmune plus calcitriol with cal-citriol alone. The median time to disease progression was significantly delayed in the Actimmune plus calcitriol arm versus calcitriol alone.

F. Role in therapy According to Micro-medex, the primary place in therapy of Actimmune is as prophylaxis against infection in patients with chronic granu-lomatous disease, and as an adjunct to conventional therapies (i.e., antimicrobial agents, bone marrow transplantation, leukocyte infusions) in these patients.

G. Other applications Actimmune may have application in the treatment of a variety of cancers (e.g., malignant melanoma, ovarian cancer), AIDS, rheumatoid arthritis, hepatitis B, and cutaneous leish-maniasis, atopic dermatitis, and keloidal scarring. There is preliminary evidence that Actimmune may benefit patients with pulmonary fibrosis.

H. Other considerations Interferon gam-ma-1b has been designated an orphan product for use in the treatment of chronic granulomatous disease, renal cell carcinoma, and severe congenital osteoporosis.

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