Population pharmacokinetics of sarilumab in patients with rheumatoid arthritis
Christine Xu (1), Yaming Su (2), Anne Paccaly (3), Vanaja Kanamaluru (1)
(1) Sanofi Genzyme, Bridgewater, NJ, USA, (2) Daiichi Sankyo, Inc, Edison, NJ, USA, (3) Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA
Objectives: To develop and characterize a population-pharmacokinetic (PK) model of sarilumab, a human mAb blocking the IL-6Rα currently in development for the treatment of rheumatoid arthritis (RA), and to describe the pharmacokinetics and assess the sources of PK variability in patients with RA.
Methods: A population-PK model was developed from data pooled across seven phase 1, one phase 2, and four phase 3 studies of sarilumab in 1770 adult patients with RA. Covariates evaluated in the analysis included demographic characteristics (eg, age, sex, race, and weight), laboratory tests of renal and liver function, drug product, antidrug antibody (ADA), C-reactive protein (CRP) levels, disease activity score (DAS28-CRP), and concomitant medication. Potential covariates were identified using a stepwise forward-addition and backward-deletion strategy, and the final population-PK model was evaluated by visual predictive check and bootstrap.
Results: The pharmacokinetics of sarilumab were adequately described by a 2-compartment, target-mediated drug disposition model with parallel linear and nonlinear Michaelis-Menten elimination, and first-order absorption. At steady state, AUC0-14 days increased 2-fold with an increase in dose from 150 to 200 mg subcutaneously (SC) every 2 weeks (q2w). The main source of intrinsic PK variability was body weight, with lower body weight associated with higher PK exposure. As compared with a typical 71-kg (median) patient, AUC0-14 days for an 83-kg patient was 23% and 20% lower and AUC0-14 days for a 62-kg patient was 25% and 20% higher for sarilumab 150 and 200 mg q2w, respectively, indicating limited clinical relevance. Other statistically significant covariates, the magnitude of which were of limited clinical importance, included sex, albumin, creatinine clearance, baseline CRP, ADA status, and drug product. Age, race, and concomitant methotrexate were not identified as significant covariates. The variability of sarilumab pharmacokinetics was not associated with baseline DAS28-CRP or prior use of biologics, based on the post hoc analyses.
Conclusions: The population-PK model described the pharmacokinetics of sarilumab SC in patients with RA and allowed for prediction of individual patient exposure. The main source of intrinsic PK variability was body weight. No dose adjustment is required.