Soulele Konstantina, Karalis Vangelis
a Department of Pharmacy, School of Health Sciences , National and Kapodistrian University of Athens , Athens , Greece.
b Institute of Applied and Computational Mathematics (IACM)/Foundation of Research and Technology Hellas (FORTH) , Heraklion, Crete , Greece.
Xenobiotica. 2019 Apr;49(4):446-456. doi: 10.1080/00498254.2018.1463117. Epub 2018 Apr 27.
Ezetimibe is a potent cholesterol absorption inhibitor, with an erratic pharmacokinetic (PK) profile, attributed to an extensive enterohepatic recirculation (EHC). The aim of this study was to develop a population PK model able to adequately characterize the complex distribution processes of total ezetimibe. The analysis was performed on the individual concentration-time data obtained from 28 healthy subjects who participated in a bioequivalence study comparing two oral ezetimibe formulations. The population PK analysis was performed using nonlinear mixed effect modeling, where different EHC models were developed and evaluated for their performance. Total ezetimibe pharmacokinetics was best described by a four-compartment model featuring EHC through the inclusion of an additional gallbladder compartment, which was assumed to release drug at specific time-intervals consistent with food intake. The final PK model was able to adequately estimate the population pharmacokinetic parameters and to allow for a formal characterization of the pharmacokinetic profile and the secondary peaks due to enterohepatic recirculation.
依折麦布是一种强效的胆固醇吸收抑制剂，其药代动力学（PK）特征不稳定，这归因于广泛的肠肝循环（EHC）。本研究的目的是建立一个群体PK模型，能够充分表征依折麦布总量的复杂分布过程。分析是基于从28名健康受试者获得的个体浓度-时间数据进行的，这些受试者参与了一项比较两种口服依折麦布制剂的生物等效性研究。使用非线性混合效应模型进行群体PK分析，在此过程中开发并评估了不同的EHC模型的性能。通过纳入一个额外的胆囊隔室来体现EHC的四室模型能够最好地描述依折麦布总量的药代动力学，该胆囊隔室被假定在与食物摄入一致的特定时间间隔释放药物。最终的PK模型能够充分估计群体药代动力学参数，并对药代动力学特征以及由肠肝循环引起的二次峰进行正式表征。
