Actimmune

CLINICAL PHARMACOLOGY

General

Interferons bind to specific cell surface receptors and initiate a sequence of intracellular events that lead to the transcription of interferon-stimulated genes. The three major groups of interferons (alpha, beta, gamma) have partially overlapping biological activities that include immunoregulation such as increased resistance to microbial pathogens and inhibition of cell proliferation. Type 1 interferons (alpha and beta) bind to the alpha/beta receptor. Interferon-gamma binds to a different cell surface receptor and is classified as Type 2 interferon. Specific effects of interferon-gamma include the enhancement of the oxidative metabolism of macrophages, antibody dependent cellular cytotoxicity (ADCC), activation of natural killer (NK) cells, and the expression of Fc receptors and major histocompatibility antigens.

Chronic Granulomatous Disease (CGD) is an inherited disorder of leukocyte function caused by defects in the enzyme complex responsible for phagocyte superoxide generation. ACTIMMUNE (interferon gamma 1 b) does not increase phagocyte superoxide production even in treatment responders.1

In severe, malignant osteopetrosis (an inherited disorder characterized by an osteoclast defect, leading to bone overgrowth, and by deficient phagocyte oxidative metabolism), a treatment-related enhancement of superoxide production by phagocytes was observed. ACTIMMUNE (interferon gamma 1 b) was found to enhance osteoclast function in vivo.2-4

In both disorders, the exact mechanism(s) by which ACTIMMUNE (interferon gamma 1 b) has a treatment effect has not been established. Changes in superoxide levels during ACTIMMUNE (interferon gamma 1 b) therapy do not predict efficacy and should not be used to assess patient response to therapy.

Pharmacokinetics

The intravenous, intramuscular, and subcutaneous pharmacokinetics of ACTIMMUNE (interferon gamma 1 b) have been investigated in 24 healthy male subjects following single-dose administration of 100 mcg/m2. ACTIMMUNE (interferon gamma 1 b) 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 (interferon gamma 1 b) 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 (interferon gamma 1 b) by the intravenous, intramuscular and subcutaneous routes. In vitroperfusion 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 1 b) (Interferon gamma- lb) in patients with Chronic Granulomatous Disease (CGD), was performed to determine whether ACTIMMUNE (interferon gamma 1 b) 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 (interferon gamma 1 b) 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 (interferon gamma 1 b) (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 (interferon gamma 1 b) group (30 on placebo versus 14 on ACTIMMUNE (interferon gamma 1 b) , p=0.002) and the total number and rate of serious infections including recurrent events (56 on placebo versus 20 on ACTIMMUNE (interferon gamma 1 b) , p= < 0.0001). Moreover, the length of hospitalization for the treatment of all clinical events provided evidence highly supportive of an ACTIMMUNE (interferon gamma 1 b) treatment benefit. Placebo patients required three times as many inpatient hospitalization days for treatment of clinical events compared to patients receiving ACTIMMUNE (interferon gamma 1 b) (1493 versus 497 total days, p=0.02). An ACTIMMUNE (interferon gamma 1 b) 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 (interferon gamma 1 b) compared to placebo across all groups.. The beneficial effect of ACTIMMUNE (interferon gamma 1 b) therapy was observed throughout the entire study, in which the mean duration of ACTIMMUNE (interferon gamma 1 b) administration was 8.9 months/patient.

Effects in Osteopetrosis

A controlled, randomized study in patients with severe, malignant osteopetrosis was conducted with ACTIMMUNE (interferon gamma 1 b) administered subcutaneously three times weekly. Sixteen patients were randomized to receive either ACTIMMUNE (interferon gamma 1 b) 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 (interferon gamma 1 b) 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 (interferon gamma 1 b) plus or minus calcitriol for at least 6 months had reduced trabecular bone volume compared to baseline.

REFERENCES

1. The International Chronic Granulomatous Disease Cooperative Study Group. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. N Engl J Med 324: 509-16, 1991.

2. Beard CJ, Key L, Newburger PE, Ezekowitz RAB, et al. Neutrophil defect associated with malignant infantile osteopetrosis. J Lab Clin Med 108: 498-505, 1986.

3. Shankar L, Gerritsen EJA, and Key LL. Osteopetrosis: pathogenesis and rationale for the use of interferon-γ-1 b. Biodrugs 7: 23-29, 1997.

4. Key LL, Rodriguiz RM, Willi SM. Long-term treatment of osteopetrosis with recombinant human interferon gamma. N Engl J Med 24: 1594-1599,1995.

Last reviewed on RxList: 2/19/2008
This monograph has been modified to include the generic and brand name in many instances.

A A A

Actimmune - User Reviews

Actimmune User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Actimmune sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Women's Health

Find out what women really need.


NIH talks about Ebola on WebMD