Cao Zhihai, Wang Zilong, Zhang Qian, Zhang Wei, Zheng Liang, Hu Wei
Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China.
School of Pharmacy, Anhui Medical University, Hefei 230032, China.
Pharmaceuticals (Basel). 2025 Mar 18;18(3):425. doi: 10.3390/ph18030425.
Tofacitinib is mainly used in the adult population for immune-mediated inflammatory diseases. There is little information available on the pharmacokinetics of tofacitinib in pediatric patients, populations with hepatic impairment and renal impairment, and patients with drug-drug interactions (DDIs). This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of tofacitinib in the populations mentioned above. We developed the PBPK models in PK-Sim and evaluated the models with observed clinical PK data. The Monte Carlo algorithm was used for parameter identification. The adult PBPK model accurately simulated the pharmacokinetic profiles of all administration scenarios. The geometric mean fold errors for the predicted/observed maximum concentration and area under the curve are 1.17 and 1.16, respectively. The extrapolated models accurately simulated the pharmacokinetic characteristics of tofacitinib. The pediatric patients aged 12-to-<18 years and 2-to-<6 years need to adjust the dose to 4 mg BID and 1.7 mg BID, respectively, to achieve comparable steady-state exposures to 5 mg BID in adults. The populations with moderate hepatic impairment and severe renal impairment need to reduce the dose to 50% and 75% of the original dose, respectively. Tofacitinib should be reduced to 50% and 65% of the original dose for concomitant use with fluconazole and ketoconazole, respectively, and increased to 150% of the original dose for concomitant use with rifampicin. We developed a tofacitinib PBPK model and extrapolated it to special populations and DDIs. The predictive results of the models can help the rational use of tofacitinib in these populations.
托法替布主要用于成人免疫介导的炎症性疾病。关于托法替布在儿科患者、肝功能损害和肾功能损害人群以及存在药物相互作用（DDIs）患者中的药代动力学信息很少。本研究旨在建立一个基于生理的药代动力学（PBPK）模型，以预测托法替布在上述人群中的药代动力学。我们在PK-Sim中开发了PBPK模型，并用观察到的临床药代动力学数据对模型进行评估。采用蒙特卡罗算法进行参数识别。成人PBPK模型准确模拟了所有给药方案的药代动力学特征。预测/观察到的最大浓度和曲线下面积的几何平均倍数误差分别为1.17和1.16。外推模型准确模拟了托法替布的药代动力学特征。12至<18岁和2至<6岁的儿科患者分别需要将剂量调整为4mg每日两次和1.7mg每日两次，以实现与成人每日两次5mg相当的稳态暴露量。中度肝功能损害和重度肾功能损害人群分别需要将剂量降低至原剂量的50%和75%。托法替布与氟康唑和酮康唑合用时，应分别降至原剂量的50%和65%，与利福平合用时，应增至原剂量的150%。我们开发了托法替布PBPK模型，并将其外推至特殊人群和药物相互作用情况。模型的预测结果有助于托法替布在这些人群中的合理使用。
