Reig-López Javier, García-Arieta Alfredo, Mangas-Sanjuán Víctor, Merino-Sanjuán Matilde
Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46010 Valencia, Spain.
División de Farmacología y Evaluación Clínica, Departamento de Medicamentos de Uso Humano, Agencia Española de Medicamentos y Productos Sanitarios, Calle Campezo 1, Edificio 8, 28022 Madrid, Spain.
Pharmaceutics. 2021 May 13;13(5):709. doi: 10.3390/pharmaceutics13050709.
Atorvastatin (ATS) is the gold-standard treatment worldwide for the management of hypercholesterolemia and prevention of cardiovascular diseases associated with dyslipidemia. Physiologically based pharmacokinetic (PBPK) models have been positioned as a valuable tool for the characterization of complex pharmacokinetic (PK) processes and its extrapolation in special sub-groups of the population, leading to regulatory recognition. Several PBPK models of ATS have been published in the recent years, addressing different aspects of the PK properties of ATS. Therefore, the aims of this review are (i) to summarize the physicochemical and pharmacokinetic characteristics involved in the time-course of ATS, and (ii) to evaluate the major highlights and limitations of the PBPK models of ATS published so far. The PBPK models incorporate common elements related to the physicochemical aspects of ATS. However, there are important differences in relation to the analyte evaluated, the type and effect of transporters and metabolic enzymes, and the permeability value used. Additionally, this review identifies major processes (lactonization, P-gp contribution, ATS-Ca solubility, simultaneous management of multiple analytes, and experimental evidence in the target population), which would enhance the PBPK model prediction to serve as a valid tool for ATS dose optimization.
阿托伐他汀（ATS）是全球治疗高胆固醇血症以及预防与血脂异常相关心血管疾病的金标准疗法。基于生理的药代动力学（PBPK）模型已被定位为表征复杂药代动力学（PK）过程及其在特定人群亚组中外推的宝贵工具，并得到了监管认可。近年来已发表了多个阿托伐他汀的PBPK模型，涉及阿托伐他汀PK特性的不同方面。因此，本综述的目的是：（i）总结阿托伐他汀时间进程中涉及的物理化学和药代动力学特征；（ii）评估迄今已发表的阿托伐他汀PBPK模型的主要亮点和局限性。这些PBPK模型包含与阿托伐他汀物理化学方面相关的共同要素。然而，在所评估的分析物、转运体和代谢酶的类型及作用以及所使用的渗透率值方面存在重要差异。此外，本综述确定了主要过程（内酯化、P-糖蛋白的作用、阿托伐他汀钙的溶解度、多种分析物的同时处理以及目标人群中的实验证据），这些过程将增强PBPK模型预测，使其成为阿托伐他汀剂量优化的有效工具。
