Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; Department of Chemical and Pharmaceutical Engineering, Sofia University, Sofia, Bulgaria.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
Eur J Pharm Sci. 2021 Jul 1;162:105812. doi: 10.1016/j.ejps.2021.105812. Epub 2021 Mar 20.
The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic consequences. The source of variability can be traced back to interindividual variability in physiology, differences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug interactions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic constipation, anorexia and cachexia) to drug absorption variability has not been firmly established yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area.
口服药物的吸收常常受到显著的变异性的困扰，这可能会产生严重的治疗后果。变异性的来源可以追溯到个体间生理学的变异性、特殊人群（年龄和疾病相关）的差异、药物和制剂特性或食物-药物相互作用。一些因素对药物药代动力学变异性影响的临床证据正在增加：例如胃 pH 值和排空时间、小肠液特性、儿科和老年人的差异以及胃肠道解剖结构的手术改变。然而，结肠因素变异性（通过时间、流体成分、微生物组）、性别差异（男性与女性）和与肠道相关的疾病（慢性便秘、厌食和恶病质）与药物吸收变异性之间的联系尚未得到确凿证实。与此同时，制药行业提供了一种降低口服药物药代动力学变异性的方法：临床证据表明，在药物开发过程中采用的制剂方法可以降低口服暴露的变异性。本综述概述了口服药物暴露变异性的主要驱动因素和潜在的克服方法，同时突出了现有知识差距并指导该领域的未来研究。
