Roferon-A Pharmacology, Pharmacokinetics, Studies, Metabolism - Peginterferon alfa-2b

Roferon-A Pharmacology, Pharmacokinetics, Studies, Metabolism - Peginterferon alfa-2b

CLINICAL PHARMACOLOGY

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, immunomodulating 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 dose of PEG-Intron, the mean absorption half-life (t ¹ / ₂ k _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. After multiple 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. Single dose peginterferon alfa-2b pharmacokinetics following a subcutaneous 1.0 µg/kg dose suggest the clearance of peginterferon alfa-2b is reduced by approximately half in patients with impaired renal function (creatinine clearance <50 mL/minute).

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 µg/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 than interferon alfa-2b.

Pharmacokinetic data from geriatric patients (> 65 years of age) treated with a single subcutaneous dose of 1.0 µg/kg of PEG-Intron showed no remarkable differences in C _max , AUC, clearance, or elimination half-life from those obtained in younger patients.

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.

Drug Interactions:   It is not known if PEG-Intron therapy causes clinically significant drug-drug interactions with drugs metabolized by the liver in patients with hepatitis C. In 12 healthy subjects known to be CYP2D6 extensive metabolizers, a single subcutaneous dose of 1 µg/kg PEG-Intron did not inhibit CYP1A2, 2C8/9, 2D6, hepatic 3A4 or N-acetyltransferase; the effects of PEG-Intron on CYP2C19 were not assessed.

CLINICAL STUDIES

A randomized study compared treatment with PEG-Intron (0.5, 1.0, or 1.5 µg/kg once weekly SC) to treatment with INTRON A, (3 million units three times weekly SC) in 1219 adults with chronic hepatitis from HCV infection. The patients were not previously treated with interferon alfa, had compensated liver disease, detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis. Patients were treated for 48 weeks and were followed for 24 weeks post-treatment. Seventy percent of all patients were infected with HCV genotype 1, and 74% of all patients had high baseline levels of HCV RNA (more than 2 million copies per mL of serum), two factors known to predict poor response to treatment.

Response to treatment was defined as undetectable HCV RNA and normalization of ALT at 24 weeks post-treatment. The response rates to the 1.0 and 1.5 µg/kg PEG-Intron doses were similar to each other and were both higher than response rates to INTRON A. (See Table 1 )

Patients with both viral genotype 1 and high serum levels of HCV RNA at baseline were less likely to respond to treatment with PEG-Intron. Among patients with the two unfavorable prognostic variables, 8% (12/157) responded to PEG-Intron treatment and 2% (4/169) responded to INTRON A. Doses of PEG-Intron higher than the recommended dose did not result in higher response rates in these patients.

Patients receiving PEG-Intron with viral genotype 1 had a response rate of 14% (28/199) while patients with other viral genotypes had a 45% (43/96) response rate.

Ninety-six percent of the responders in the PEG-Intron groups and 100% of responders in the INTRON A group first cleared their viral RNA by week 24 of treatment. See DOSAGE AND ADMINISTRATION.

The treatment response rates were similar in men and women. Response rates were lower in African American and Hispanic patients and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians the number of non-Caucasians studied (9% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors.

Liver biopsies were obtained before and after treatment in 60% of patients. A modest reduction in inflammation compared to baseline that was similar in all four treatment groups was observed.