Ritlecitinib 是一种在肝细胞癌家族抑制剂中表达的口服 Janus 激酶 3/酪氨酸激酶，正在进行针对斑秃、白癜风、溃疡性结肠炎、克罗恩病和类风湿关节炎的并行临床开发。正如研究同时读出的那样，群体药代动力学模型开发的战略规划和需要进行评估以确保及时做出决定。其中包括来自 2014 年 12 月至 2021 年 7 月期间 12 项临床试验的健康参与者和患者的数据：7 项针对健康参与者和器官损伤的 I 期研究，5 项针对类风湿关节炎患者的 II/III 期研究，溃疡性结肠炎、斑秃和白癜风。群体药代动力学模型由逐步程序组成，以适应数据可用性和模型用于回答临床开发问题的应用。在模型更新的每次迭代中，都会利用之前的信息和新数据重新估计下一个模型的参数。对 Ritlecitinib 群体药代动力学模型进行了三次模型开发生命周期迭代，以支持斑秃、白癜风和溃疡性结肠炎研究读数。第 1 次迭代中基于健康参与者数据（以及一些类风湿性关节炎和斑秃数据）的初始结构建模为第 2 次迭代中的综合协变量测试提供了一个平台，并在第 3 次迭代中进行了模型评估和常客先验方法的实施。最终模型为具有一级吸收和直接响应非稳态清除率以及由外周室浓度驱动的生物利用度的两室模型。本方法通过积累的数据证明了三种群体药代动力学模型的演变，解决了与以下相关的临床药物开发问题NCT02309827、NCT02684760、NCT02958865、NCT02969044、NCT03232905、NCT03732807、NCT04016077、NCT03715829、NCT04037865、NCT0400 4663、NCT04634565、NCT02974868。© 2023。作者。

Ritlecitinib is an oral Janus kinase 3/tyrosine kinase expressed in hepatocellular carcinoma family inhibitor undergoing parallel clinical development for alopecia areata, vitiligo, ulcerative colitis, Crohn's disease, and rheumatoid arthritis.As studies read out simultaneously, strategic planning of population pharmacokinetic model development and evaluation is required to ensure timely decisions.Data from healthy participants and patients from 12 clinical trials between December 2014 and July 2021 were included: seven phase I studies in healthy participants and organ impairment, five phase II/III studies in patients with rheumatoid arthritis, ulcerative colitis, alopecia areata, and vitiligo. Population pharmacokinetic models consisted of stepwise procedures to accommodate data availability and the model's application to answering clinical development questions. At each iteration of the model update, parameters of the next model were re-estimated by leveraging previous information and new data.Three model development lifecycle iterations of the ritlecitinib population pharmacokinetic model were conducted to support alopecia areata, vitiligo, and ulcerative colitis study readouts. Initial structural modeling based on healthy participant data (and some rheumatoid arthritis and alopecia areata data) in iteration 1 provided a platform for comprehensive covariate testing during iteration 2, and model evaluation and implementation of the frequentist prior approach in iteration 3. The final model was a two-compartment model with first-order absorption and direct-response non-stationary clearance and bioavailability driven by concentrations in the peripheral compartment.The present approach demonstrated the evolution of three population pharmacokinetic models with accumulating data, addressed clinical drug development questions related to systemic exposures of ritlecitinib, and informed the approved product label.NCT02309827, NCT02684760, NCT02958865, NCT02969044, NCT03232905, NCT03732807, NCT04016077, NCT03715829, NCT04037865, NCT04004663, NCT04634565, NCT02974868.© 2023. The Author(s).