Objective: To determine if higher serum exposure during subcutaneous (SC) abatacept treatment was associated with an increased infection risk in adult patients with early rheumatoid arthritis (RA).
Methods: Data from AVERT-2 (Assessing Very Early Rheumatoid arthritis Treatment-2, NCT02504268), a randomized, placebo-controlled study in anticitrullinated protein antibody- positive patients with early RA, were analyzed. A post hoc population pharmacokinetic (PPK) analysis was performed. Association between steady-state abatacept concentration exposures (steady-state time-averaged serum concentration, steady-state trough serum concentration, steady-state maximum serum concentration) and first infection was evaluated using Kaplan-Meier plots of probability versus time on treatment and Cox proportional-hazards models.
Results: PK of SC abatacept was defined as a linear 2-compartment model with first-order absorption and elimination; higher body weight was the only covariate with a clinically relevant effect in the final PPK model. Infections occurred in 330/693 (47.6%; 11/693 [1.6%] serious infections) patients treated with abatacept+methotrexate (MTX) and 134/301 (44.5%; 4/301 [1.3%] serious infections), with abatacept placebo+MTX. Exposure-response analysis demonstrated no exposure relationship for an increased risk of first infection with concomitant use of MTX and glucocorticoids during the induction period, baseline glucocorticoid use, or higher than median body weight at baseline (> 70 kg).
Conclusion: This exposure-response analysis of AVERT-2 showed no increase in the risk of first infection, regardless of abatacept exposure level in patients with RA treated with SC abatacept. Similarly, no effect on the risk of first infection was found for concomitant MTX and glucocorticoid use in patients with RA treated with SC abatacept+MTX.