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Population pharmacokinetic and pharmacodynamic modeling of etanercept using logistic regression analysis

Howard Lee, Hui C. Kimko, Mark Rogge, Diane Wang, Ivan Nestorov and Carl C. Peck

Georgetown University, Immunex Corporation

Objectives: To develop a population pharmacokinetic (PK) and pharmacodynamic model of etanercept in patients with rheumatoid arthritis (RA), using the American College of Rheumatology response criterion of 20 % improvement (ACR20) as a binary clinical outcome variable.

Methods: Concentration data from 25 subjects administered 25 mg subcutaneous (SC) etanercept twice weekly for 24 weeks (42 samples per subject) were pooled with concentrations from 77 subjects (3 samples per subject), enrolled in a 24- week, randomized, double-blind study comparing 25 mg and 50 mg SC etanercept twice weekly. The cumulative area under the concentration-time curve (AUC) was calculated and used as an exposure variable. ACR20 was the binomial clinical outcome. ACR20 data from another 80 placebo- treated patients enrolled in a randomized and double-blind phase III study were used to describe the placebo time course of ACR20. A logistic regression analysis using NONMEM was applied to describe an exposure-time-effect relationship, and the 95% confidence interval (CI) was constructed by bootstrapping 1,000 times.

Results: The population standard of apparent clearance was 0.117 L/hr (95% CI: 0.108-0.130 L/hr) for Caucasian females and 0.138 L/hr for Caucasian males (95% CI: 0.118-0.163 L/hr). The interindividual and interoccasion variability were 41.1% and 27.6%, respectively. The absorption half-life was 20.9 hrs and elimination half-life was 95.4 hrs. The model- predicted percentage of patients achieving ACR20 at 6 months following 25 mg SC twice weekly dosing was 54.9%, comparable to the observed 52.9%.

Conclusion: The population PK analysis confirmed that etanercept is slowly absorbed and then eliminated after SC administration and the logistic model linking cumulative AUC with ACR20 adequately characterized the time course of clinical improvement in RA patients receiving etanercept.