{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:21:41Z","timestamp":1792012901269,"version":"4.4.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A physiologically-based pharmacokinetic (PBPK) model integrating a target-mediated drug disposition (TMDD) structure was built for adults and extrapolated to pediatric patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The PBPK model successfully predicted and verified the pharmacokinetics (PKs) of TCZ in children aged &amp;lt; 2 years and 2\u201317 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 &amp;lt;30 kg, including infants aged &amp;lt;2 years and children aged 2\u201317 years, and a 4-6-8 mg\/kg sequence for children aged 2\u201317 years weighing \u226530 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  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