Abstract
Abatacept population pharmacokinetics (PK) and exposure-response (E-R) models for selective efficacy end points were developed using phase 2 and 3 study data in patients with rheumatoid arthritis treated with abatacept (intravenous [IV] or subcutaneous [SC]), followed by simulations. Two efficacy end points were assessed in the E-R analyses: Disease Activity Score in 28 joints (DAS28) and American College of Rheumatology response criteria for 20/50/70% improvement (ACR20/50/70). The analyses were performed with data from 11 clinical studies for the population PK analysis and from 3 clinical studies for the E-R analyses (DAS28 and ACR20/50/70). The PK of abatacept were time invariant and can be described by a linear 2-compartment model with first-order elimination and with zero-order IV infusion or first-order absorption for SC abatacept. Baseline body weight was the only clinically meaningful covariate; that is, abatacept clearance and volume of central compartment increased with increasing baseline body weight. Steady-state trough concentration (C(minss) ) of abatacept was identified as the best exposure predictor of DAS28 response compared with other exposure measures. In addition, the E-R relationship was the same for IV and SC abatacept. Similar results were confirmed in the ACR20/50/70 E-R analyses. Efficacy responses increased with increasing C(minss) and a near-maximal response was associated with C(minss) ≥10 μg/mL. The model-based analyses confirmed that the weight-tiered ∼10 mg/kg IV and fixed 125 mg SC abatacept dosing regimens are comparable and achieved plateau responses, by delivering C(minss) ≥10 μg/mL in RA patients across all body weights.