Department of Pharmacy, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, PR China; Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, PR China.
Department of Pharmacy, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, PR China; Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, PR China.
Eur J Pharm Sci. 2024 Aug 1;199:106807. doi: 10.1016/j.ejps.2024.106807. Epub 2024 May 24.
Ustekinumab (UST), a fully human immunoglobulin G1 κ monoclonal antibody, exhibiting high affinity for the p40 subunit shared by IL-12 and IL-23, which play key roles in the pathogenesis of inflammatory bowel disease (IBD). By scaling the physiologically-based pharmacokinetic modeling (PBPK) model of UST in adult patients with IBD, we aim to predict effective dosages for UST in pediatric patients, thereby offering a more practical dosing regimen for real-world applications. In this work, a PBPK model for UST in adult patients with IBD has been developed using PK-Sim and Mobi. Advanced ontogeny model has been incorporated to extrapolate the model to pediatric patients. The simulation results showed that the fold errors of the predicted and observed values of the area under the curve (AUC) and peak plasma concentration (C) were between 0.79 and 1.73. For children aged 6-18, it is recommended to administer the drug per kilogram of body weight, at the model-recommended dose, to achieve a median AUC similar to that of the adult reference population post-administration. This comprehensive model construction enables us to comprehensively and extensively explore the pharmacokinetic characteristics of UST in pediatric patients of different age groups, providing robust support for clinical applications and personalized drug therapy.
乌司奴单抗(UST)是一种完全人源化 IgG1κ 单克隆抗体,对 IL-12 和 IL-23 的 p40 亚单位具有高亲和力,而这两个亚单位在炎症性肠病(IBD)的发病机制中起着关键作用。通过对 IBD 成年患者的乌司奴单抗基于生理的药代动力学模型(PBPK)进行缩放,我们旨在预测儿科患者使用乌司奴单抗的有效剂量,从而为实际应用提供更实用的给药方案。在这项工作中,使用 PK-Sim 和 Mobi 开发了 IBD 成年患者的 UST PBPK 模型。已纳入先进的个体发生模型,将模型外推至儿科患者。模拟结果表明,预测和观察到的 AUC 和峰血浆浓度(C)的曲线下面积(AUC)和峰血浆浓度(C)的比值误差在 0.79 到 1.73 之间。对于 6-18 岁的儿童,建议按体重给药,按照模型推荐的剂量,以达到与成人参考人群给药后相似的中位数 AUC。这种全面的模型构建使我们能够全面广泛地探索不同年龄组儿科患者的 UST 药代动力学特征,为临床应用和个性化药物治疗提供有力支持。