Population Pharmacokinetic and Pharmacodynamic Modeling of Lusutrombopag, a Newly Developed Oral Thrombopoietin Receptor Agonist, in Healthy Subjects
Population Pharmacokinetic and Pharmacodynamic Modeling of Lusutrombopag, a Newly Developed Oral Thrombopoietin Receptor Agonist, in Healthy Subjects
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DOI：
10.1007/s40262-016-0411-6
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发表时间：
2016-11-01
影响因子：
4.5
通讯作者：
Wajima, Toshihiro
中科院分区：
文献类型：
--
作者：
Katsube, Takayuki;Ishibashi, Toru;Wajima, Toshihiro
本研究的目的是建立一个人群药代动力学(PK)/药效学（PD）模型，用于描述口服lusutrombopag后血浆lusutrombopag浓度和血小板反应，并评估PK/PD谱中的协变量。采用78名健康成人口服单次和多次（14天，每日一次）给药后的2539例血浆lusutrombopag浓度数据和1408例血小板计数数据，建立了人群PK/PD模型。探讨了PK和PK/PD模型中的协变量，包括受试者年龄、体重、性别和种族。选择具有一阶吸收速率和滞后时间的三室模型作为PK模型。PD模型选用三转运单血小板室模型，药物效应和血小板生成反馈采用s型E （max）模型。PK和PK/PD模型分别很好地描述了血浆lusutrombopag浓度和血小板反应。体重是PK的重要协变量。非日本受试者（白人和黑人/非裔美国人受试者）的生物利用度比日本受试者低13%，而使用PK/PD模型模拟的血小板反应谱在日本和非日本受试者之间相似。在测试的背景数据中，包括年龄、性别和种族（日本人或非日本人），PD敏感性没有显著的协变量。以lusutrombopag为研究对象建立了种群PK/PD模型，该模型能较好地预测其PK/PD分布。该模型可作为lusutrombopag药物开发的基本PK/PD模型。
The aim of this study was to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model for describing plasma lusutrombopag concentrations and platelet response following oral lusutrombopag dosing and for evaluating covariates in the PK/PD profiles.A population PK/PD model was developed using a total of 2539 plasma lusutrombopag concentration data and 1408 platelet count data from 78 healthy adult subjects following oral single and multiple (14-day once-daily) dosing. Covariates in PK and PK/PD models were explored for subject age, body weight, sex, and ethnicity.A three-compartment model with first-order rate and lag time for absorption was selected as a PK model. A three-transit and one-platelet compartment model with a sigmoid E (max) model for drug effect and feedback of platelet production was selected as the PD model. The PK and PK/PD models well described the plasma lusutrombopag concentrations and the platelet response, respectively. Body weight was a significant covariate in PK. The bioavailability of non-Japanese subjects (White and Black/African American subjects) was 13 % lower than that of Japanese subjects, while the simulated platelet response profiles using the PK/PD model were similar between Japanese and non-Japanese subjects. There were no significant covariates of the tested background data including age, sex, and ethnicity (Japanese or non-Japanese) for the PD sensitivity.A population PK/PD model was developed for lusutrombopag and shown to provide good prediction for the PK/PD profiles. The model could be used as a basic PK/PD model in the drug development of lusutrombopag.