General: The biological activity of PEG-Intron is derived from its interferon alfa-2b moiety. Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface and initiate a complex sequence of intracellular events. These include the induction of certain enzymes, suppression of cell proliferation, immunomod-ulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and inhibition of virus replication in virus-infected cells. Interferon alfa upregulates the Th1 T-helper cell subset in in vitro studies. The clinical relevance of these findings is not known.

Pharmacodynamics: PEG-Intron raises concentrations of effector proteins such as serum neopterin and 2'5'oligoadenylate synthetase, raises body temperature, and causes reversible decreases in leukocyte and platelet counts. The correlation between the in vitro and in vivo pharmacologic and pharmacodynamic and clinical effects is unknown.

Pharmacokinetics: Following a single subcutaneous (SC) dose of PEG-Intron, the mean absorption half-life (t 1/2k_a) was 4.6 hours. Maximal serum concentrations (C_max) occur between 15-44 hours post-dose, and are sustained for up to 48-72 hours. The C_max and AUC measurements of PEG-Intron increase in a dose-related manner. Aftermultiple dosing, there is an increase in bioavailability of PEG-Intron. Week 48 mean trough concentrations (320 pg/mL; range 0, 2960) are approximately 3-fold higher than Week 4 mean trough concentrations (94 pg/mL; range 0, 416). The mean PEG-Intron elimination half-life is approximately 40 hours (range 22 to 60 hours) in patients with HCV infection. The apparent clearance of PEG-Intron is estimated to be approximately 22.0 mL/hr· kg. Renal elimination accounts for 30% of the clearance. Pegylation of interferon alfa-2b produces a product (PEG-Intron) whose clearance is lower than that of non-pegylated interferon alfa-2b. When compared to INTRON A, PEG-Intron (1.0 mg/kg) has approximately a seven-fold lower mean apparent clearance and a five-fold greater mean half-life permitting a reduced dosing frequency. At effective therapeutic doses, PEG-Intron has approximately ten-fold greater C_max and 50-fold greater AUC thaninterferon alfa-2b.

Following multiple dosing of PEG-Intron (1 mcg/kg SC given every week for four weeks) the clearance of PEG-Intron is reduced by a mean of 17% in patients with moderate renal impairment (creatinine clearance 30-49 mL/min) and by a mean of 44% in patients with severe renal impairment (creatinine clearance 10-29 mL/min) compared to subjects with normal renal function. Clearance was similar in patients with severe renal impairment not on dialysis and patients who are receiving hemodialysis. The dose of PEG-Intron for monothera-py should be reduced in patients with moderate or severe renal impairment (See DOSAGE AND ADMINISTRATION: DOSE REDUCTION). REBETOL should not be used in patients with creatinine clearance < 50 mL/min (See REBETOL Package Insert, WARNINGS).

During the 48 week treatment period with PEG-Intron, no differences in the pharmacokinetic profiles were observed between male and female patients with chronic hepatitis C infection.

Brand Name: Roferon-A alfa-2b
Generic Name: Peginterferon alfa-2b

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