Pharmacodynamics

Interferons bind to specific receptors on the cell surface initiating intracellular signaling via a complex cascade of protein-protein interactions leading to rapid activation of gene transcription. Interferon-stimulated genes modulate many biological effects including the inhibition of viral replication in infected cells, inhibition of cell proliferation and immunomodulation. The clinical relevance of these in vitro activities is not known.

PEGASYS stimulates the production of effector proteins such as serum neopterin and 2, 5-oligoadenylate synthetase.

Maximal serum concentrations (C_max) and AUC increased in a nonlinear dose related manner following administration of 90 to 270 mg of PEGASYS. Maximal serum concentrations (C_max) occur between 72 to 96 hours post-dose.

Week 48 mean trough concentrations (16 ng/mL; range 4 to 28) at 168 hours post-dose are approximately 2-fold higher than week 1 mean trough concentrations (9 ng/mL; range 0 to 15). Steady-state serum levels are reached within 5 to 8 weeks of once weekly dosing. The peak to trough ratio at week 48 is approximately 2. The mean systemic clearance in healthy subjects given PEGASYS was 94 mL/h, which is approximately 100-fold lower than that for interferon alfa-2a (ROFERON-A). The mean terminal half- life after sc dosing in patients with chronic hepatitis C was 80 hours (range 50 to 140 hours) compared to 5 hours (range 3.7 to 8.5 hours) for ROFERON-A.

Gender and Age

PEGASYS administration yielded similar pharmacokinetics in male and female healthy subjects. The AUC was increased from 1295 to 1663 ng·h/mL in subjects older than 62 years taking 180 mg PEGASYS, but peak concentrations were similar (9 vs. 10 ng/mL) in those older and younger than 62 years.

Pediatric Patients

In a population pharmacokinetics study, 14 children 2 to 8 years of age with CHC received PEGASYS based on their body surface area (BSA of the child x 180 mg/1.73m²). The clearance of PEGASYS in children was nearly 4-fold lower compared to the clearance reported in adults.

Steady state trough levels in children with the BSA-adjusted dosing were similar to trough levels observed in adults with 180 mg fixed dosing. Time to reach the steady state in children is approximately 12 weeks, whereas in adults, steady state is reached within 5 to 8 weeks. In these children receiving the BSA adjusted dose, the mean exposure (AUC) during the dosing interval is predicted to be 25% to 70% higher than that observed in adults receiving 180 mg fixed dosing. The safety and effectiveness of PEGASYS in patients below the age of 18 years have not been established (see PRECAUTIONS: Pediatric Use).

Renal Dysfunction

In patients with end stage renal disease undergoing hemodialysis, there is a 25% to 45% reduction in PEGASYS clearance (see PRECAUTIONS: Renal Impairment).

The pharmacokinetics of ribavirin following administration of COPEGUS have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of COPEGUS in patients with creatinine clearance <50 mL/min. Therefore, patients with creatinine clearance <50 mL/min should not be treated with COPEGUS (see WARNINGS and DOSAGE AND ADMINISTRATION).

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