Model-informed safety management of tocilizumab for pediatric sJIA: a PBPK approach for dose-escalation and vaccination timing.

INTRODUCTION

Tocilizumab (TCZ), an anti-interleukin-6 receptor (IL-6R) biologic agent, is commonly used to treat systemic juvenile idiopathic arthritis (sJIA); however, the optimal dosing strategy for susceptible children and the timing of administration for safe attenuated live vaccines remain unclear. This study aimed to determine the optimal dose-escalation regimen for TCZ in children with sJIA, as well as to investigate the recommended live-vaccine schedules for pediatric patients exposed to this drug.

METHODS

A physiologically-based pharmacokinetic (PBPK) model integrating a target-mediated drug disposition (TMDD) structure was built for adults and extrapolated to pediatric patients.

RESULTS

The PBPK model successfully predicted and verified the pharmacokinetics (PKs) of TCZ in children aged < 2 years and 2-17 years. The predicted PK data were within two-fold of the observed data. According to the simulations, dose-escalation strategies were proposed to mitigate early hypersensitivity reactions: a 6-8-12 mg/kg sequence for patients weighing <30 kg, including infants aged <2 years and children aged 2-17 years, and a 4-6-8 mg/kg sequence for children aged 2-17 years weighing ≥30 kg. Furthermore, PBPK models indicated that, for pediatric patients of all ages, the advocated timing of live-attenuated vaccination is approximately 55 to 70 days after treatment cessation, provided that the underlying disease activity is closely monitored.

DISCUSSION: Our study illustrated that PBPK models can provide a valuable tool to predict the PKs of large macromolecules in children across the age continuum, ultimately informing precision drug-treatment decisions and vaccination regimens for the pediatric sJIA population.