A population pharmacokinetic (PK) analysis of etanercept in patients with juvenile rheumatoid arthritis (JRA)

Abstract

Objective To estimate the population PK parameters of etanercept in pediatric JRA patients. Methods 353 concentrations from 69 JRA patients aged 4 - 17 yrs administered subcutaneous (SC) 0.4 mg/Kg etanercept twice weekly for 3 months in a double-blind placebo controlled study were used for analysis. PK samples were drawn at random times on days 1 and 15; at the end of months 1, 2, and 3; and 30 days after the discontinuation of the drug. Mixed effect model analysis with FO method in NONMEM (Ver. 5.0) and bootstrapping was performed. Diagnostic plots and decreased objective function value (>10.83) were criteria used. Results One-compartment linear absorption PK model with interindividual variability on CL, V, Ka, covariates (sex, BSA) on CL, and body weight on V was developed: (See table). Conclusion The final population PK model adequately described etanercept PK profiles for twice weekly SC dosing of 0.4 mg/kg, which can be summarized as a slow absorption and long half lives, ranging from 70 (males) to 100 hours (females). This result could be used for a clinical trial simulation of 0.8 mg/Kg SC etanercept once weekly regimen for patients with JRA. Clinical Pharmacology & Therapeutics (2004) 75, P53–P53; doi: 10.1016/j.clpt.2003.11.199 Table 1. Parameter and Structural Model Covariates Population Mean (95% C.I.¶) Interindividual Variability CV§ (95% C.I.¶) C/F (L/hr)/F = 0.0576 (F) or 0.0772 (M) × (BSA/1.071)1.41 Female 0.0576 (0.0525–0.0657) 29% (22–35%) Male 0.0772 (0.066–0.0870) V/F(L) = 7.88 × (body weight in kg/30.8) 7.88 (3.03–8.69) 87% (25–2020%) Ka (1/hr) = 0.05 0.05 (0.01–0.99) 215% (29–1977%) Residual Error Additive Error (mg/L, SD) Proportional Error, CV 0.00103 (0.00052–0.025) 30% (27–36%)