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Population pharmacokinetic‐pharmacodynamic (PK‐PD) modeling of etanercept in patients with juvenile rheumatoid arthritis (JRA) using a dichotomous clinical endpoint
Author(s) -
Yim D.,
Zhou H.,
Peck C. C.,
Lee H.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.246
Subject(s) - etanercept , nonmem , medicine , pharmacodynamics , population , erythrocyte sedimentation rate , clinical trial , juvenile rheumatoid arthritis , clinical pharmacology , rheumatoid arthritis , pharmacokinetics , statistics , arthritis , pharmacology , mathematics , environmental health
Background Realistic PK‐PD models should incorporate the perceived clinical outcome of drug treatment. In the case of JRA, therapeutic outcome is judged according to a dichotomous scale (improved or not). We developed a PK‐PD model for etanercept using six clinical component variables, which comprise the definition of improvement (DOI), assessed as “improved” if three or more of the components decrease by more than 30% of baseline values. Methods Clinical trial data of etanercept in 69 patients with JRA were used. The six component variables were percentage changes from baselines of global assessments by the physician (MDGA), patients or guardians (PTGA), functional ability (FA), number of active joints (AJC), number of joints with limitation of motion (LOM) and erythrocyte sedimentation rate (ESR). Each variable was fitted using the E max model with individual predicted etanercept concentration or cumulative AUC. (NONMEM Ver. 5.1.1.) The dichotomous DOI was determined according to the criterion of 30% improvement in at least 3 of the 6 individual predicted variables. Results E max and EC 50 estimates are shown in the table. Three hundred and thirty eight points out of 422 (80.1%) individual predicted DOI values matched with the observed DOI values. Conclusions A PK‐PD model for a dichotomous PD parameter was developed using component variables. This approach will help researchers to quantify the pharmacologic effects assessed by dichotomous clinical outcome variables. (See Table) Clinical Pharmacology & Therapeutics (2005) 77 , P92–P92; doi: 10.1016/j.clpt.2004.12.246 Estimated Emax and EC50Component Variable Pharmacokinetic Parameter Used Estimated E max (%) Estimated EC 50MDGA Cumulative AUC 63.5 1510 mg/L × h FA Cumulative AUC 55.2 5250 mg/L × h AJC Cumulative AUC 54.5 1750 mg/L × h LOM Cumulative AUC 50.7 1260 mg/L × h PTGA Serum concentration 52.3 904 μg/L ESR Serum concentration 44.2 98.8 μg/L