Drug Metabolism and Pharmacokinetics, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Drug Metab Dispos. 2013 Jul;41(7):1367-74. doi: 10.1124/dmd.112.050542. Epub 2013 Apr 25.
In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits P-glycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as digoxin when the maximum concentration of inhibitor at steady state divided by IC₅₀ ([I₁]/IC₅₀) is ≥0.1 or concentration of inhibitor based on highest approved dose dissolved in 250 ml divide by IC₅₀ ([I₂]/IC₅₀) is ≥10. In this article, refined criteria are presented, determined by receiver operating characteristic analysis, using IC₅₀ values generated by 23 laboratories. P-gp probe substrates were digoxin for polarized cell-lines and N-methyl quinidine or vinblastine for P-gp overexpressed vesicles. Inhibition of probe substrate transport was evaluated using 15 known P-gp inhibitors. Importantly, the criteria derived in this article take into account variability in IC₅₀ values. Moreover, they are statistically derived based on the highest degree of accuracy in predicting true positive and true negative digoxin DDI results. The refined criteria of [I₁]/IC₅₀ ≥ 0.03 and [I₂]/IC₅₀ ≥ 45 and FDA criteria were applied to a test set of 101 in vitro-in vivo digoxin DDI pairs collated from the literature. The number of false negatives (none predicted but DDI observed) were similar, 10 and 12%, whereas the number of false positives (DDI predicted but not observed) substantially decreased from 51 to 40%, relative to the FDA criteria. On the basis of estimated overall variability in IC₅₀ values, a theoretical 95% confidence interval calculation was developed for single laboratory IC₅₀ values, translating into a range of [I₁]/IC₅₀ and [I₂]/IC₅₀ values. The extent by which this range falls above the criteria is a measure of risk associated with the decision, attributable to variability in IC₅₀ values.
在 2012 年食品和药物管理局（FDA）关于药物相互作用（DDI）的指南草案中，当新的分子实体抑制 P-糖蛋白（P-gp）时，在稳态时抑制剂的最大浓度除以 IC₅₀（[I₁]/IC₅₀）≥0.1 或根据最高批准剂量溶解在 250 毫升中的抑制剂浓度除以 IC₅₀（[I₂]/IC₅₀）≥10 时，可能需要进行与 P-gp 底物（如地高辛）的临床 DDI 研究。在本文中，通过使用 23 个实验室生成的 IC₅₀ 值进行接收者操作特征分析，提出了经过改进的标准。P-gp 探针底物为极化细胞系的地高辛和 P-gp 过度表达囊泡的 N-甲基奎尼丁或长春碱。使用 15 种已知的 P-gp 抑制剂评估探针底物转运的抑制作用。重要的是，本文中得出的标准考虑了 IC₅₀ 值的变异性。此外，它们是根据预测真正的地高辛 DDI 阳性和阴性结果的最高准确性统计得出的。[I₁]/IC₅₀≥0.03 和 [I₂]/IC₅₀≥45 的改进标准和 FDA 标准应用于从文献中整理的 101 对地高辛体外-体内 DDI 对的测试集。没有预测但观察到 DDI 的假阴性（未预测但观察到 DDI）的数量相似，为 10%和 12%，而预测但未观察到 DDI 的假阳性（预测但未观察到 DDI）的数量从 51 个显著减少到 40%，与 FDA 标准相比。基于 IC₅₀ 值的总体估计变异性，为单个实验室 IC₅₀ 值开发了理论 95%置信区间计算，转化为 [I₁]/IC₅₀ 和 [I₂]/IC₅₀ 值的范围。该范围高于标准的程度是与决策相关的风险的度量，归因于 IC₅₀ 值的变异性。
