Clinical Trial Center/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, West China Hospital of Sichuan University, Chengdu, China.
The Office of Clinical Trial Management/Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Br J Clin Pharmacol. 2022 May;88(5):2084-2095. doi: 10.1111/bcp.15130. Epub 2021 Nov 13.
The pharmacokinetics (PK) of hetrombopag were found to be nonlinear across evaluated dose ranges. The aim of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PopPK/PD) model and to provide a reasonable expected therapeutic dose for a future confirmatory clinical study of hetrombopag.
Nonlinear mixed-effects modelling was performed using pooled 2168 hetrombopag concentrations and 1526 platelet counts from 72 healthy subjects and 32 chronic idiopathic thrombocytopenic purpura (ITP) patients from two phase I studies and one phase II study. The final model was evaluated via goodness-of-fit plots, visual predictive check and nonparametric bootstrap. Simulations from the validated PopPK/PD model were used to devise an expected therapeutic dose for later confirmatory clinical study.
The pharmacokinetic data of hetrombopag were well described by a modified target-mediated drug disposition (TMDD) model with dual sequential first-order absorption. Mean parameter estimates (interindividual variability) were CL/F 7.66 L/h (63.5%), V /F 30.0 L (77.2%) and K 0.693/h (87.1%). The pharmacodynamic profile was well described by a five-compartment lifespan model with four-transit and one-platelet compartments. Simulation results suggested that chronic ITP patients following 10 mg once-daily hetrombopag would able to achieve an ideal platelet count level (50-200 × 10 /L).
TMDD was the primary reason leading to nonlinear PK profile of hetrombopag. Our PK/PD modelling and simulation results support 10 mg once-daily as the recommended therapeutic dose for chronic ITP patients in subsequent confirmatory clinical study of hetrombopag.
研究发现，在评估的剂量范围内，替莫泊芬的药代动力学（PK）呈非线性。本研究旨在建立一个基于机制的群体药代动力学/药效学（PopPK/PD）模型，并为替莫泊芬的未来验证性临床研究提供合理的预期治疗剂量。
使用来自两项 I 期研究和一项 II 期研究的 72 名健康受试者和 32 名慢性特发性血小板减少性紫癜（ITP）患者的 2168 个替莫泊芬浓度和 1526 个血小板计数数据，采用非线性混合效应模型进行建模。通过拟合度图、可视化预测检查和非参数 bootstrap 对最终模型进行评估。从验证的 PopPK/PD 模型中进行模拟，以设计用于后续验证性临床研究的预期治疗剂量。
替莫泊芬的药代动力学数据通过改良的靶向介导药物处置（TMDD）模型与双顺序一级吸收得到了很好的描述。平均参数估计值（个体间变异性）为 CL/F 7.66 L/h（63.5%）、V/F 30.0 L（77.2%）和 K 0.693/h（87.1%）。药效学特征通过一个具有四个转运和一个血小板隔室的五隔室寿命模型得到了很好的描述。模拟结果表明，每日一次接受 10 mg 替莫泊芬的慢性 ITP 患者将能够达到理想的血小板计数水平（50-200×10/L）。
TMDD 是导致替莫泊芬 PK 呈非线性的主要原因。我们的 PK/PD 建模和模拟结果支持每日一次 10 mg 作为替莫泊芬在慢性 ITP 患者后续验证性临床研究中的推荐治疗剂量。
