Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Clinigen Healthcare Limited, Pitcairn House, Crown Square, First Avenue, Burton-on-Trent, Staffordshire, DE14 2WW, United Kingdom
Pharmacotherapeutic group: Immunostimulants, Cytokines and immunomodulators
ATC code: L03AB03
Interferons are a family of functionally related proteins synthesised by eukaryotic cells in response to viruses and a variety of natural and synthetic stimuli. The real mechanism of action of interferon gamma-1b in CGD is still unknown. Findings related to superoxide anion production remain unequivocal. However, it is presumed that interferon gamma-1b increases macrophage cytotoxicity by enhancing the respiratory burst via generation of toxic oxygen metabolites capable of mediating the killing of intracellular micro-organisms. It increases HLA-DR expression on macrophages and augments Fc receptor expression, which results in increased antibody-dependent cell-mediated cytotoxicity.
In a placebo-controlled clinical trial in 128 patients with CGD, IMMUKIN was shown to reduce the frequency of serious infections during the trial period of 12 months by 77% in patients treated with IMMUKIN compared to 30% in the placebo group (p=0.0006). The overwhelming majority of these patients were also receiving prophylactic antimicrobial therapy.
Data on the safety and efficacy of IMMUKIN in 37 CGD patients under the age of 3 years was pooled from 4 uncontrolled post-marketing studies and 2 sequential post-marketing surveillance studies. The rate of serious infections per patient-year in this uncontrolled group was similar to the rate observed in the IMMUKIN treatment groups in controlled trials.
In severe, malignant osteopetrosis (inherited disorder characterised 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.
In a controlled randomised study in 16 patients with severe, malignant osteopetrosis, IMMUKIN in combination with calcitriol was shown to reduce the frequency of serious infections versus calcitriol alone. In an analysis which combined data from two clinical studies, 19 of 24 patients treated with IMMUKIN in combination with or without calcitriol for at least 6 months had reduced trabecular bone volume compared to baseline. The clinical relevance of this observed decrease in IMMUKIN treated patients versus a control group could not be established.
Following subcutaneous single dose administration of 0.05 mg/m² of IMMUKIN in healthy male subjects, a mean peak plasma concentration (Cmax) of 631 pg/mL (CV=33.82%) interferon gamma-1b was observed after a mean time (tmax) of 8 hours (CV=23.99%). The mean area under the curve (AUC0-∞) was 8.3 ng h/mL. In cancer patients a comparable (dose normalised) exposure is observed and AUC increased dose proportional over the 0.1–0.5 mg/m² dose range. I.m. administration showed peak plasma concentrations after about 4 hours. The apparent fraction of drug absorbed after i.m. or s.c. injection was greater than 89%. A dose proportionality has been demonstrated after i.v.and i.m. administration for doses ranging from 0.1 mg/m² to 2.5 mg/m² and after s.c. administration from 0.1 mg/m² to 0.5 mg/m².
The volume of distribution at the steady state after bolus i.v.or s.c. administration ranged from 10.9 to 47.93 L. In healthy male subjects, there was no accumulation of interferon gamma-1b after 12 consecutive daily injections of 0.1 mg/m². The mean value of the Mean Residence Time (MRT) after s.c. administration in the range of 0.1-0.5 mg/m² is 10.95 h (S.D. ± 2.40 h).
The metabolism of cloned interferons falls within the natural handling of proteins. Interferon gamma-1b was not detected in the urine of healthy male subjects following administration of 0.1 mg/m² via i.v., i.m. or s.c. routes. In vitro hepatic and renal perfusion studies demonstrate that the liver and kidneys are capable of clearing interferon gamma-1b from perfusate. Preclinical studies in nephrectomised animals demonstrated a reduction in the clearance of interferon gamma-1b from blood; however prior nephrectomy did not prevent elimination. The mean value of the apparent clearance following s.c. single dose administration in the range of 0.1-0.5 mg/m² was 2.87 L/min (S.D. ± 1.48).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction, local tolerance and skin sensitisation.
An increased incidence of abortion has been observed in pregnant non-human primates, which received the drug in doses manifold higher than that recommended for human use.
Interferon gamma caused increased apoptosis in rat uterus and placenta and in human cytotrophoblast cells. Teratogenicity was observed in mice at lower doses than the human dose. No teratogenicity was observed in rats and in primates up to 100 times the human dose.
Administration of very high doses of interferon gamma to juvenile male mice caused reduced epididymal and testes weights, reduced sperm counts, sperm abnormalities and reduced mating performance and fertility. These effects are considered not relevant for human use at the indicated dose levels.
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