Etanercept is cleared slowly from the body. The half-life is long, approximately 70 hours. Clearance is approximately 0.066 l/hr in patients with rheumatoid arthritis, somewhat lower than the value of 0.11 l/hr observed in healthy volunteers. Additionally, the pharmacokinetics of etanercept in rheumatoid arthritis patients, ankylosing spondylitis and plaque psoriasis patients are similar. There is no apparent pharmacokinetic difference between males and females. Linearity Dose proportionality has not been formally evaluated, but there is no apparent saturation of clearance across the dosing range.
Special populations Renal impairment Although there is elimination of radioactivity in urine after administration of radiolabelled etanercept to patients and volunteers, increased etanercept concentrations were not observed in patients with acute renal failure. The presence of renal impairment should not require a change in dosage. Hepatic impairment Increased etanercept concentrations were not observed in patients with acute hepatic failure. The presence of hepatic impairment should not require a change in dosage. Elderly The impact of advanced age was studied in the population pharmacokinetic analysis of etanercept serum concentrations.
Clearance and volume estimates in patients aged 65 to 87 years were similar to estimates in patients less than 65 years of age. Paediatric population Paediatric patients with juvenile idiopathic arthritis In a polyarticular-course juvenile idiopathic arthritis trial with etanercept, 69 patients (aged 4 to 17 years) were administered 0.4 mg etanercept/kg twice weekly for three months. Serum concentration profiles were similar to those seen in adult rheumatoid arthritis patients. The youngest children (4 years of age) had reduced clearance (increased clearance when normalised by weight) compared with older children (12 years of age) and adults.
Simulation of dosing suggests that while older children (10– 17 years of age) will have serum levels close to those seen in adults, younger children will have appreciably lower levels. Paediatric patients with plaque psoriasis Patients with paediatric plaque psoriasis (aged 4 to 17 years) were administered 0.8 mg/kg (up to a maximum dose of 50 mg per week) of etanercept once weekly for up to 48 weeks. The mean serum steady-state trough concentrations ranged from 1.6 to 2.1 mcg/ml at weeks 12, 24, and 48.
These mean concentrations in patients with paediatric plaque psoriasis were similar to the concentrations observed in patients with juvenile idiopathic arthritis (treated with 0.4 mg/kg etanercept twice weekly, up to maximum dose of 50 mg per week). These mean concentrations were similar to those seen in adult patients with plaque psoriasis treated with 25 mg etanercept twice-weekly. 5.3 Preclinical safety data In the toxicological studies with etanercept, no dose-limiting or target organ toxicity was evident. Etanercept was considered to be non-genotoxic from a battery of in vitro and in vivo studies. 29