Population pharmacokinetic and pharmacodynamic modeling of etanercept using logistic regression analysis
| Autor: | Carl C. Peck, Howard Lee, Diane Wang, Mark Rogge, Ivan Nestorov, Hui C. Kimko |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
musculoskeletal diseases
Male medicine.medical_specialty Population Enzyme-Linked Immunosorbent Assay Logistic regression Placebo Models Biological Drug Administration Schedule Receptors Tumor Necrosis Factor Etanercept Arthritis Rheumatoid Pharmacokinetics Double-Blind Method Internal medicine medicine Humans Pharmacology (medical) education Pharmacology education.field_of_study business.industry Middle Aged medicine.disease Confidence interval Surgery NONMEM Logistic Models Rheumatoid arthritis Area Under Curve Immunoglobulin G Female business medicine.drug Half-Life |
| Zdroj: | Clinical pharmacology and therapeutics. 73(4) |
| ISSN: | 0009-9236 |
| Popis: | Objective Our objective was to develop a population pharmacokinetic and pharmacodynamic model of etanercept in patients with rheumatoid arthritis, with the American College of Rheumatology response criterion of 20% improvement (ACR20) used as a binary clinical outcome variable. Methods Concentration-time profiles from 25 subjects, administered 25 mg subcutaneous etanercept twice weekly for 24 weeks, were pooled with data from 77 subjects, enrolled in a 24-week, randomized, double-blind study comparing 25 mg and 50 mg subcutaneous etanercept twice weekly. The cumulative area under the concentration-time curve (AUC) was used as the exposure variable, and ACR20 was the binomial clinical outcome. ACR20 data from another 80 placebo-treated patients enrolled in a randomized, double-blind phase III study were used to describe the placebo time course of ACR20. A logistic regression analysis with NONMEM was applied to describe the exposure-response relationship, and the 95% confidence intervals (95% CIs) were constructed by bootstrapping 1000 times. Results The population mean apparent clearance was 0.117 L/h (95% CI, 0.108-0.130 L/h) for white female patients and 0.138 L/h (95% CI, 0.118-0.163 L/h) for white male patients. Interindividual variability and interoccasion variability were 41.1% and 27.6%, respectively. The mean absorption half-life was 20.9 hours, and the elimination half-life was 95.4 hours. An improved response profile in male patients was shown, but the multiplicative factor between slope on cumulative AUC between male and female patients was not statistically significant (1.69; 95% CI, 0.37-9.99). The model-predicted percentage of patients achieving ACR20 at 6 months after dosing of 25 mg subcutaneously twice weekly was 54.9%, comparable to the observed 52.9%. Conclusion The population pharmacokinetic analysis confirmed that etanercept is slowly absorbed and eliminated after subcutaneous administration. The logistic model linking cumulative AUC with ACR20 adequately characterized the time course of clinical improvement in patients with rheumatoid arthritis receiving etanercept. Clinical Pharmacology & Therapeutics (2003) 73, 348–365; doi: 10.1016/S0009-9236(02)17635-1 |
| Databáze: | OpenAIRE |
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