(T-079) Population Pharmacokinetic Analysis to Characterize Pharmacokinetics of Sarilumab in Pediatric Participants with Polyarticular-Course Juvenile Idiopathic Arthritis
Pharmacometrician Sanofi, Morristown, NJ USA, United States
Objectives: Sarilumab is a monoclonal antibody that binds to the interleukin-6 receptor (IL-6R) with high affinity. Inhibition of IL-6 signaling through blockade of the IL-6R has been demonstrated to be effective in pediatric patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). The objective of this study was to develop a population pharmacokinetic (PopPK) model to characterize sarilumab pharmacokinetics (PK) in pediatric patients with pcJIA and to assess the influence of intrinsic and extrinsic factors on sarilumab PK in pediatric patients with pcJIA.
Methods: The analysis was conducted using PK data from 101 pediatric patients with pcJIA (aged 2 to 17 years) enrolled in a phase 2 study (NCT02776735) with at least 52-week treatment. A previously developed PopPK base model for adult rheumatoid arthritis (RA) patients1 was utilized as a starting point in the model development. For the base model selection, sensitivity analyses were conducted to evaluate the impact of several factors on model performance, including baseline weight or time-varying weight, fixed or estimated allometric scaling factors, different combinations of inter-individual variability, using pcJIA pediatric data only or pooled data from 159 RA adult patients from the selected studies (NCT01328522, NCT01850680, and NCT02057250) and pcJIA pediatric patients. The effect of covariates such as gender, age, creatinine clearance normalized by body surface area, albumin, and C-reactive protein measurements on sarilumab PK was evaluated. The final model was validated through visual predictive checks and bootstrapping and was used to generate individual estimates of PK exposures. Simulations were conducted at the approved dose regimens (3 mg/kg every two weeks [q2w] for Group A of ≥30 kg and 4 mg/kg q2w for Group B of < 30 kg) using a virtual pediatric population (N=2000) from the National Health and Nutrition Examination Survey enabling PK exposure comparison between pediatric and adult patients.
Results: The PK of sarilumab in pediatric patients with pcJIA was well described by a two-compartment model with parallel linear and Michaelis-Menten elimination and first-order absorption. Baseline body weight with fixed allometric scaling was included in the final structural base model due to its best overall performance. Although albumin was identified as the only statistically significant covariate, it was not considered to be clinically relevant. All other tested covariates had no statistically significant effect on sarilumab PK in this population. Simulation results suggested that the recommended dosing regimens for pediatric patients with pcJIA achieve sarilumab exposure similar to the approved 200 mg q2w regimen in adult patients with RA.
Conclusions: The developed PopPK model adequately described the sarilumab PK in pediatric patients with pcJIA and supported the recommended doses of sarilumab.
Citations: [1] Xu C, Su Y, Paccaly A, Kanamaluru V, et al. Population Pharmacokinetics of Sarilumab in Patients with Rheumatoid Arthritis. Clin Pharmacokinet. 58(11):1455-1467; 2019.
Keywords: Sarilumab, population pharmacokinetics, pcJIA
