Evaluation of etanercept dose reduction in patients with rheumatoid arthritis using pharmacokinetic/pharmacodynamic modeling and simulation

In this study, we attempt to explore the feasibility of alternative dosing regimens of etanercept in patients with rheumatoid arthritis (RA) using pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation.All data used for estimation of PK/PD model parameters were collected from previously published literatures. American College of Rheumatology (ACR) 20/50/70 response rate and a disease activity score in 28 joints (DAS28) was selected as the principal clinical endpoint for further PK/PD modeling. The cumulative AUC (area under the concentration-time curve) of etanercept for different dosing regimens was calculated based on the final PK model and was then linked to the time course of clinical endpoints. Ten different dosing regimens were simulated in this study.The PK model that best fit the serum concentration-time data for etanercept was a one-compartment model with first order absorption and elimination. Based on the PK/PD analysis, the relationship between the predicted cumulative AUC of etanercept to the ACR 20/50/70 response rate and DAS28 score was well characterized by Emax logistic and inhibitory Emax model, respectively. In our simulations, the following dosing regimens that are equally effective to current recommended dosage of 25 mg twice weekly (b.i.w.): (1) 25 mg once weekly (q.w.); (2) 50 mg every 2 weeks (q2w); (3) 25 mg b.i.w. for 3 months and 25 mg q2w thereafter; and (4) 50 mg q.w. for 3 months and 50 mg q2w thereafter.In this study, the clinical data was well described by the models developed, and several alternative dosing regimens were proposed. Further clinical studies in patients are still needed to confirm our findings.