Progress in Prediction and Interpretation of Clinically Relevant Metabolic Drug-Drug Interactions: a Minireview Illustrating Recent Developments and Current Opportunities.
Progress in Prediction and Interpretation of Clinically Relevant Metabolic Drug-Drug Interactions: a Minireview Illustrating Recent Developments and Current Opportunities.
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DOI：
10.1007/s40495-017-0082-5
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发表时间：
2017
影响因子：
--
通讯作者：
Yu L
中科院分区：
文献类型：
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作者：
Fowler S;Morcos PN;Cleary Y;Martin-Facklam M;Parrott N;Gertz M;Yu L
本文综述了代谢药物相互作用（DDI）预测的最新进展。我们强调了成功预测的领域，并说明了在科学知识或技术限制使我们无法充分自信的领域取得的进展。文中强调了几个成功的例子。对bitopertin的研究表明，如何将体外和临床数据整合起来，以提供基于模型的药代动力学和药物相互作用的理解。以伊鲁替尼为例，讨论了使用插值预测来获得未经测试的DDI的明确剂量建议，并以依利司他和阿勒替尼为例，说明了在新药应用包装中使用DDI预测来代替临床研究。阿勒替尼也是一个有趣的例子，剂量调整是不必要的，因为主要代谢物的活性足以补偿母体药物暴露的变化。“不寻常的”细胞色素P450 （CYP）和非CYP酶负责代谢清除的例子表明，继续开发我们的体外试剂和技术的重要性。利用悬浮在全血浆中的人肝细胞进行的时间依赖性抑制试验可以改善DDI预测，这说明了继续开发和完善体外试验的重要性。在过去的10年里，在cypp介导的代谢性ddi领域已经有了高度的机制理解，能够根据临床前研究预测临床结果。高质量的体外数据和基于生理的药代动力学模型的结合现在可以用于前瞻性地评估DDI风险，并且越来越多地被接受来代替专门的临床研究。本文的在线版本（doi:10.1007/s40495-017-0082-5）包含补充材料，仅供授权用户使用。
This review gives a perspective on the current “state of the art” in metabolic drug-drug interaction (DDI) prediction. We highlight areas of successful prediction and illustrate progress in areas where limits in scientific knowledge or technologies prevent us from having full confidence. Several examples of success are highlighted. Work done for bitopertin shows how in vitro and clinical data can be integrated to give a model-based understanding of pharmacokinetics and drug interactions. The use of interpolative predictions to derive explicit dosage recommendations for untested DDIs is discussed using the example of ibrutinib, and the use of DDI predictions in lieu of clinical studies in new drug application packages is exemplified with eliglustat and alectinib. Alectinib is also an interesting case where dose adjustment is unnecessary as the activity of a major metabolite compensates sufficiently for changes in parent drug exposure. Examples where “unusual” cytochrome P450 (CYP) and non-CYP enzymes are responsible for metabolic clearance have shown the importance of continuing to develop our repertoire of in vitro regents and techniques. The time-dependent inhibition assay using human hepatocytes suspended in full plasma allowed improved DDI predictions, illustrating the importance of continued in vitro assay development and refinement. During the past 10 years, a highly mechanistic understanding has been developed in the area of CYP-mediated metabolic DDIs enabling the prediction of clinical outcome based on preclinical studies. The combination of good quality in vitro data and physiologically based pharmacokinetic modeling may now be used to evaluate DDI risk prospectively and are increasingly accepted in lieu of dedicated clinical studies. The online version of this article (doi:10.1007/s40495-017-0082-5) contains supplementary material, which is available to authorized users.