Kostewicz Edmund S, Aarons Leon, Bergstrand Martin, Bolger Michael B, Galetin Aleksandra, Hatley Oliver, Jamei Masoud, Lloyd Richard, Pepin Xavier, Rostami-Hodjegan Amin, Sjögren Erik, Tannergren Christer, Turner David B, Wagner Christian, Weitschies Werner, Dressman Jennifer
Institute of Pharmaceutical Technology, Goethe University, Frankfurt/Main, Germany.
Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, United Kingdom.
Eur J Pharm Sci. 2014 Jun 16;57:300-21. doi: 10.1016/j.ejps.2013.09.008. Epub 2013 Sep 21.
Drug absorption from the gastrointestinal (GI) tract is a highly complex process dependent upon numerous factors including the physicochemical properties of the drug, characteristics of the formulation and interplay with the underlying physiological properties of the GI tract. The ability to accurately predict oral drug absorption during drug product development is becoming more relevant given the current challenges facing the pharmaceutical industry. Physiologically-based pharmacokinetic (PBPK) modeling provides an approach that enables the plasma concentration-time profiles to be predicted from preclinical in vitro and in vivo data and can thus provide a valuable resource to support decisions at various stages of the drug development process. Whilst there have been quite a few successes with PBPK models identifying key issues in the development of new drugs in vivo, there are still many aspects that need to be addressed in order to maximize the utility of the PBPK models to predict drug absorption, including improving our understanding of conditions in the lower small intestine and colon, taking the influence of disease on GI physiology into account and further exploring the reasons behind population variability. Importantly, there is also a need to create more appropriate in vitro models for testing dosage form performance and to streamline data input from these into the PBPK models. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the current status of PBPK models available. The current challenges in PBPK set-ups for oral drug absorption including the composition of GI luminal contents, transit and hydrodynamics, permeability and intestinal wall metabolism are discussed in detail. Further, the challenges regarding the appropriate integration of results from in vitro models, such as consideration of appropriate integration/estimation of solubility and the complexity of the in vitro release and precipitation data, are also highlighted as important steps to advancing the application of PBPK models in drug development. It is expected that the "innovative" integration of in vitro data from more appropriate in vitro models and the enhancement of the GI physiology component of PBPK models, arising from the OrBiTo project, will lead to a significant enhancement in the ability of PBPK models to successfully predict oral drug absorption and advance their role in preclinical and clinical development, as well as for regulatory applications.
药物从胃肠道（GI）的吸收是一个高度复杂的过程，取决于众多因素，包括药物的物理化学性质、制剂特性以及与胃肠道潜在生理特性的相互作用。鉴于制药行业当前面临的挑战，在药物产品开发过程中准确预测口服药物吸收的能力变得愈发重要。基于生理学的药代动力学（PBPK）建模提供了一种方法，能够根据临床前的体外和体内数据预测血浆浓度-时间曲线，从而为支持药物开发过程各个阶段的决策提供有价值的资源。虽然PBPK模型在识别体内新药开发的关键问题方面已经取得了不少成功，但仍有许多方面需要解决，以最大限度地发挥PBPK模型预测药物吸收的效用，包括加深我们对小肠下段和结肠情况的了解、考虑疾病对胃肠道生理学的影响以及进一步探究人群变异性背后的原因。重要的是，还需要创建更合适的体外模型来测试剂型性能，并简化从这些模型输入到PBPK模型的数据。作为口服生物制药工具（OrBiTo）项目的一部分，本综述总结了现有PBPK模型的现状。详细讨论了口服药物吸收的PBPK模型设置中当前面临的挑战，包括胃肠道腔内内容物的组成、转运和流体动力学、通透性以及肠壁代谢。此外，关于体外模型结果的适当整合所面临的挑战，如考虑溶解度的适当整合/估计以及体外释放和沉淀数据的复杂性，也被强调为推进PBPK模型在药物开发中应用的重要步骤。预计OrBiTo项目所带来的来自更合适体外模型的体外数据的“创新性”整合以及PBPK模型胃肠道生理学组成部分的增强，将显著提高PBPK模型成功预测口服药物吸收的能力，并提升其在临床前和临床开发以及监管应用中的作用。
