In vitro and in vivo studies suggest that the biological activity of peginterferon, alpha-2b is derived from its interferon alfa-2b moiety. Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Studies with other interferons have demonstrated species specificity. However, certain monkey species, e.g., Rhesus monkeys are susceptible to pharmacodynamic stimulation upon exposure to human type 1 interferons.
Once bound to the cell membrane, interferon initiates a complex sequence of intracellular events that include the induction of certain enzymes. It is thought that this process, at least in part, is responsible for the various cellular responses to interferon, including inhibition of virus replication in virusinfected cells, suppression of cell proliferation and such immunomodulating activities as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities may contribute to interferon’s therapeutic effects.
Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exact antiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cell metabolism. This action inhibits viral replication or if replication occurs, the progeny virions are unable to leave the cell.
Peginterferon alpha-2b pharmacodynamics were assessed in a rising single-dose trial in healthy subjects by examining changes in oral temperature, concentrations of effector proteins such as serum neopterin and 2’5'-oligoadenylate synthetase (2’5'-OAS), as well as white cell and neutrophil counts. Subjects treated with peginterferon alpha-2b showed mild dose-related elevations in body temperature. Following single doses of peginterferon alpha-2b between 0.25 and 2.0 micrograms/kg/week, serum neopterin concentration was increased in a dose-related manner. Neutrophil and white cell count reductions at the end of week 4 correlated with the dose of peginterferon alpha-2b.
Peginterferon alpha-2b is a well characterized polyethylene glycol-modified (“pegylated”) derivative of interferon alfa-2b and is predominantly composed of monopegylated species. The plasma half-life of peginterferon alpha-2b is prolonged compared with nonpegylated interferon alfa-2b. Peginterferon alpha-2b has a potential to depegylate to free interferon alfa-2b. The biologic activity of the pegylated isomers is qualitatively similar, but weaker than free interferon alfa-2b.
Following subcutaneous administration, maximal serum concentrations occur between 15-44 hours post-dose, and are sustained for up to 48-72 hours post-dose.
Peginterferon alpha-2b Cmax and AUC measurements increase in a dose-related manner. Mean apparent volume of distribution is 0.99 l/kg.
Upon multiple dosing, there is an accumulation of immunoreactive interferons. There is, however, only a modest increase in biologic activity as measured by a bioassay.
Mean (SD) peginterferon alpha-2b elimination half-life is approximately 40 hours (13.3 hours), with apparent clearance of 22.0 ml/hr/kg. The mechanisms involved in clearance of interferons in man have not yet been fully elucidated. However, renal elimination may account for a minority (approximately 30%) of peginterferon alpha-2b apparent clearance.
Renal clearance appears to account for 30% of total clearance of peginterferon alpha-2b. In a single dose study (1.0 microgram/kg) in patients with impaired renal function, Cmax, AUC, and half-life increased in relation to the degree of renal impairment.
Following multiple dosing of peginterferon alpha-2b (1.0 microgram/kg subcutaneously administered every week for four weeks) the clearance of peginterferon alpha-2b is reduced by a mean of 17% in patients with moderate renal impairment (creatinine clearance 30-49 ml/minute) and by a mean of 44% in patients with severe renal impairment (creatinine clearance 15-29 ml/minute) compared to subjects with normal renal function. Based on single dose data, clearance was similar in patients with severe renal impairment not on dialysis and in patients who were receiving hemodialysis. The dose of peginterferon alpha-2b for monotherapy should be reduced in patients with moderate or severe renal impairment. Patients with creatinine clearance <50 ml/minute must not be treated with peginterferon alpha-2b in combination with ribavirin (bitherapy or tritherapy).
Because of marked inter-subject variability in interferon pharmacokinetics, it is recommended that patients with severe renal impairment be closely monitored during treatment with peginterferon alpha-2b.
The pharmacokinetics of peginterferon alpha-2b have not been evaluated in patients with severe hepatic dysfunction.
The pharmacokinetics of peginterferon alpha-2b following a single subcutaneous dose of 1.0 microgram/kg were not affected by age. The data suggest that no alteration in peginterferon alpha-2b dosage is necessary based on advancing age.
Multiple-dose pharmacokinetic properties for peginterferon alpha-2b and ribavirin (capsules and oral solution) in children and adolescent patients with chronic hepatitis C have been evaluated during a clinical study.
In children and adolescent patients receiving body surface area-adjusted dosing of peginterferon alpha-2b at 60 μg/m²/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58% (90% CI: 141-177%) higher than observed in adults receiving 1.5 μg/kg/week.
Interferon neutralising factor assays were performed on serum samples of patients who received peginterferon alpha-2b in the clinical trial. Interferon neutralising factors are antibodies which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors in patients who received peginterferon alpha-2b 0.5 micrograms/kg is 1.1%.
Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin.
Adverse events not observed in clinical trials were not seen in toxicity studies in monkeys. These studies were limited to four weeks due to the appearance of anti-interferon antibodies in most monkeys.
Reproduction studies of peginterferon alfa-2b have not been performed. Interferon alfa-2b has been shown to be an abortifacient in primates. Peginterferon alpha-2b is likely to also cause this effect. Effects on fertility have not been determined. It is not known whether the components of this medicinal product are excreted into experimental animal or human milk. Peginterferon alpha-2b showed no genotoxic potential.
The relative non-toxicity of monomethoxy-polyethylene glycol (mPEG), which is liberated from peginterferon alfa-2b by metabolism in vivo has been demonstrated in preclinical acute and subchronic toxicity studies in rodents and monkeys, standard embryo-foetal development studies and in in vitro mutagenicity assays.
When used in combination with ribavirin, peginterferon alfa-2b did not cause any effects not previously seen with either active substance alone. The major treatment-related change was a reversible, mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone.
No studies have been conducted in juvenile animals to examine the effects of treatment with peginterferon alfa-2b on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with ribavirin.
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