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Actimmune (Interferon Gamma-1B) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ACTIMMUNE ® (Interferon gamma-1b), a biologic response modifier, is a single-chain polypeptide containing 140 amino acids. Production of ACTIMMUNE is achieved by fermentation of a genetically engineered Escherichia coli bacterium containing the DNA which encodes for the human protein. Purification of the product is achieved by conventional column chromatography. ACTIMMUNE is a highly purified sterile solution consisting of non-covalent dimers of two identical 16,465 dalton monomers; with a specific activity of 20 million International Units (IU)/mg (2 × 106 IU per 0.5 mL) which is equivalent to 30 million units/mg.

ACTIMMUNE is a sterile, clear, colorless solution filled in a single-dose vial for subcutaneous injection. Each 0.5 mL of ACTIMMUNE contains: 100 mcg (2 million IU) of Interferon gamma-1b formulated in 20 mg mannitol, 0.36 mg sodium succinate, 0.05 mg polysorbate 20 and Sterile Water for Injection. Note that the above activity is expressed in International Units (1 million IU/50mcg). This is equivalent to what was previously expressed as units (1.5 million U/50mcg).

CLINICAL PHARMACOLOGY

GENERAL

Interferons are a family of functionally related, species-specific, proteins synthesized by eukaryotic cells in response to viruses and a variety of natural and synthetic stimuli. 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 such as Staphylococcus aureus, Toxoplasma gondii, Leishmania donovani, Listeria monocytogenes, and Mycobacterium avium intracellulare.

Clinical studies in patients using interferon-gamma, have revealed a broad range of biological activities including the enhancement of the oxidative metabolism of tissue macrophages, enhancement of antibody-dependent cellular cytotoxicity (ADCC) and natural killer (NK) cell activity. Additionally, effects on Fc receptor expression on monocytes and major histocompatibility antigen expression have been noted. 1,2

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. There is growing evidence that interferon-gamma interacts functionally with other interleukin molecules such as interleukin-2 and that all of the interleukins form part of a complex, lymphokine regulatory network.3 For example, interferon-gamma and interleukin-4 appear to reciprocally interact to regulate murine IgE levels; interferon-gamma can suppress IgE levels in humans. 4,5 Interferon-gamma also inhibits the production of collagen at the transcription level in human systems. 6

With respect to Chronic Granulomatous Disease (an inherited disorder characterized by deficient phagocyte oxidative metabolism), pilot clinical trials of the systemic administration of ACTIMMUNE in patients with Chronic Granulomatous Disease provided evidence for a treatment-related enhancement of phagocyte function including elevation of superoxide levels and improved killing of Staphylococcus aureus. 7,8

In severe, malignant osteopetrosis (another inherited disorder characterized by an osteoclast defect leading to bone overgrowth and deficient phagocyte oxidative metabolism),9 a treatment-related enhancement of superoxide production by phagocytes was observed in situ.10 ACTIMMUNE was found to enhance osteoclast function in vitro.11,12

PHARMACOKINETICS

The intravenous, intramuscular, and subcutaneous pharmacokinetics of ACTIMMUNE have been investigated in 24 healthy male subjects following single-dose administration of 100 mcg/m2. ACTIMMUNE is rapidly cleared after intravenous administration (1.4 liters/minute) and slowly absorbed after intramuscular or subcutaneous injection. After intramuscular or subcutaneous injection, the apparent fraction of dose absorbed was greater than 89%. The mean elimination half-life after intravenous administration of 100 mcg/m2 in healthy male subjects was 38 minutes. The mean elimination half-lives for intramuscular and subcutaneous dosing with 100 mcg/m2 were 2.9 and 5.9 hours, respectively. Peak plasma concentrations, determined by ELISA, occurred approximately 4 hours (1.5 ng/mL) after intramuscular dosing and 7 hours (0.6 ng/mL) after subcutaneous dosing. Multiple dose subcutaneous pharmacokinetic studies were conducted in 38 healthy male subjects. There was no accumulation of ACTIMMUNE after 12 consecutive daily injections of 100 mcg/m2. Pharmacokinetic studies in patients with Chronic Granulomatous Disease have not been performed.

Trace amounts of interferon-gamma were detected in the urine of squirrel monkeys following intravenous administration of 500 mcg/kg. Interferon-gamma was not detected in the urine of healthy human volunteers following administration of 100 mcg/m2 of ACTIMMUNE by the intravenous, intramuscular and subcutaneous routes. In vitro perfusion studies utilizing rabbit livers and kidneys demonstrate that these organs are capable of clearing interferon-gamma from perfusate. Studies of the administration of interferon-gamma to nephrectomized mice and squirrel monkeys demonstrate a reduction in clearance of interferon-gamma from blood; however, prior nephrectomy did not prevent elimination.

EFFECTS IN CHRONIC GRANULOMATOUS DISEASE

A randomized, double-blind, placebo-controlled study of ACTIMMUNE (Interferon gamma-1b) in patients with Chronic Granulomatous Disease (CGD), was performed to determine whether ACTIMMUNE administered subcutaneously on a three times weekly schedule could decrease the incidence of serious infectious episodes and improve existing infectious and inflammatory conditions in patients with Chronic Granulomatous Disease. One hundred twenty-eight eligible patients were enrolled on this study including patients with different patterns of inheritance. Most patients received prophylactic antibiotics. Patients ranged in age from 1 to 44 years with the mean age being 14.6 years. The study was terminated early following demonstration of a highly statistically significant benefit of ACTIMMUNE therapy compared to placebo with respect to time to serious infection (p=0.0036), the primary endpoint of the investigation. Serious infection was defined as a clinical event requiring hospitalization and the use of parenteral antibiotics. The final analysis provided further support for the primary endpoint (p=0.0006). There was a 67 percent reduction in relative risk of serious infection in patients receiving ACTIMMUNE (n=63) compared to placebo (n=65). Additional supportive evidence of treatment benefit included a twofold reduction in the number of primary serious infections in the ACTIMMUNE group (30 on placebo versus 14 on ACTIMMUNE, p=0.002) and the total number and rate of serious infections including recurrent events (56 on placebo versus 20 on ACTIMMUNE, p=<0.0001). Moreover, the length of hospitalization for the treatment of all clinical events provided evidence highly supportive of an ACTIMMUNE treatment benefit. Placebo patients required three times as many inpatient hospitalization days for treatment of clinical events compared to patients receiving ACTIMMUNE (1493 versus 497 total days, p=0.02). An ACTIMMUNE treatment benefit with respect to time to serious infection was consistently demonstrated in all subgroup analyses according to stratification factors, including pattern of inheritance, use of prophylactic antibiotics, as well as age. There was a 67 percent reduction in relative risk of serious infection in patients receiving ACTIMMUNE compared to placebo across all groups. The beneficial effect of ACTIMMUNE therapy was observed throughout the entire study, in which the mean duration of ACTIMMUNE administration was 8.9 months/patient.

EFFECTS IN OSTEOPETROSIS

A controlled, randomized study in patients with severe, malignant osteopetrosis was conducted with ACTIMMUNE administered subcutaneously three times weekly. Sixteen patients were randomized to receive either ACTIMMUNE plus calcitriol (n=11), or calcitriol alone (n=5). Patients ranged in age from 1 month to 8 years, mean 1.5 years. Treatment failure was considered to be disease progression as defined by 1) death, 2) significant reduction in hemoglobin or platelet counts, 3) a serious bacterial infection requiring antibiotics, or 4) a 50 dB decrease in hearing or progressive optic atrophy. The median time to disease progression was significantly delayed in the ACTIMMUNE plus calcitriol arm versus calcitriol alone. In the treatment arm, the median was not reached. Based on the observed data, however, the median time to progression in this arm was at least 165 days versus a median of 65 days in the calcitriol alone arm. In an analysis which combined data from a second study, 19 of 24 patients treated with ACTIMMUNE plus or minus calcitriol for at least 6 months had reduced trabecular bone volume compared to baseline.

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