Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Silver Spring, MD, USA.
Oak Ridge Institute for Science and Education (ORISE) Fellow, Oak Ridge, TN, USA.
J Clin Pharmacol. 2019 Aug;59(8):1049-1060. doi: 10.1002/jcph.1413. Epub 2019 Mar 29.
The evaluation of potential of a new molecular entity (NME) to inhibit P-glycoprotein (P-gp) in vivo is an integral part of drug development and is recommended by regulatory agencies. In this study, we compared the performance of 5 prediction methods and their associated criteria (including those from the European Medicines Agency, the US Food and Drug Administration, and the Pharmaceuticals and Medical Devices Agency of Japan) for assessing the potential of an NME to inhibit P-gp in vivo based on in vitro assessment. We collected in vitro (eg, half-maximal inhibitory concentration [IC ], fraction unbound to plasma protein) and in vivo (eg, dose, maximum concentration, change in maximum concentration or area under the plasma concentration-time curve of the substrate digoxin) data for 50 Food and Drug Administration-approved, orally administered drug products containing 53 NMEs, from the University of Washington Metabolism and Transport Drug Interaction Database, Drugs@FDA, and PubMed. All methods yielded similar accuracy with small differences in false-negative (FN) and false-positive (FP) predictions. In addition, use of ratio of the theoretical maximum gastrointestinal concentration to IC is sufficient for a reasonable prediction for these orally administered drugs as potential P-gp inhibitors based on our dataset. The FN and FP rates varied depending on the cut-off value for the ratio of the theoretical maximum gastrointestinal concentration/IC . Possible reasons underlying FP and FN results from different methods should be taken into consideration to predict in vivo P-gp inhibition.
评估新分子实体（NME）在体内抑制 P-糖蛋白（P-gp）的潜力是药物开发的一个组成部分，也是监管机构所推荐的。在这项研究中，我们比较了 5 种预测方法及其相关标准（包括欧洲药品管理局、美国食品和药物管理局以及日本药品和医疗器械管理局的标准）在基于体外评估的情况下，评估 NME 在体内抑制 P-gp 的潜力的性能。我们从华盛顿大学代谢和转运药物相互作用数据库、Drugs@FDA 和 PubMed 收集了 50 种经美国食品和药物管理局批准的、口服给予的药物产品的体外（例如，半最大抑制浓度[IC ]、与血浆蛋白结合的分数）和体内（例如，剂量、最大浓度、底物地高辛的最大浓度或血浆浓度-时间曲线下面积的变化）数据，这些药物产品包含 53 种 NME。所有方法的准确性相似，假阴性（FN）和假阳性（FP）预测的差异很小。此外，根据我们的数据集，对于这些口服给予的药物，使用理论最大胃肠道浓度与 IC 的比值足以进行合理的预测，这些药物可能是 P-gp 抑制剂。FN 和 FP 率取决于理论最大胃肠道浓度/IC 的比值的截止值。应考虑不同方法产生 FP 和 FN 结果的可能原因，以预测体内 P-gp 抑制。
