Division of Infectious Disease Pharmacology, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
Guidance and Policy Team, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
J Clin Pharmacol. 2022 Dec;62(12):1501-1506. doi: 10.1002/jcph.2119. Epub 2022 Jul 19.
Comprehensive characterization of transporter mediated drug-drug interactions (DDIs) is important to formulate clinical management strategies and ensure the safe and effective use of concomitantly administered drugs. The potential of a drug to inhibit transporters is predicted by comparing the ratio of the relevant concentration (depending on the transporter) and the half maximum inhibitory concentration to a predefined "cutoff" value. If the ratio is greater than the cutoff value, modeling approaches such as physiologically based pharmacokinetic modeling or a clinical DDI trial may be recommended. Because false-positive (in vitro data suggest the potential for a DDI, whereas no significant DDI is observed in vivo) and false-negative (in vitro data does not suggest the potential for a DDI, whereas significant DDI is observed in vivo) outcomes have been observed, there is interest in exploring additional approaches to facilitate prediction of transporter-mediated DDIs. The idea of assessing changes in the concentration of endogenous biomarkers (which are substrates of clinically relevant transporters) to gain insight on the potential for a drug to inhibit transporter activity has received widespread attention. This brief report describes how endogenous biomarkers may help to expand the DDI assessment toolkit, highlights some current knowledge gaps, and outlines a conceptual framework that may complement the current paradigm of predicting the potential for transporter-mediated DDIs.
全面描述药物-药物相互作用（DDI）的转运体介导作用对于制定临床管理策略和确保同时给予的药物的安全和有效使用非常重要。通过比较相关浓度（取决于转运体）与半最大抑制浓度的比值与预设的“截止”值，可以预测药物抑制转运体的潜力。如果比值大于截止值，则可能推荐使用基于生理的药代动力学模型或临床 DDI 试验等建模方法。由于已经观察到假阳性（体外数据表明存在 DDI 的潜力，而体内观察到没有显著的 DDI）和假阴性（体外数据不表明存在 DDI 的潜力，而体内观察到显著的 DDI）结果，因此人们有兴趣探索其他方法来促进转运体介导的 DDI 的预测。评估内源性生物标志物（临床相关转运体的底物）浓度变化以深入了解药物抑制转运体活性的潜力的想法引起了广泛关注。本简要报告描述了内源性生物标志物如何有助于扩展 DDI 评估工具包，强调了一些当前的知识空白，并概述了一个概念框架，该框架可能补充预测转运体介导的 DDI 潜力的当前范例。
