Comparing Various In Vitro Prediction Criteria to Assess the Potential of a New Molecular Entity to Inhibit Organic Anion Transporting Polypeptide 1B1
Comparing Various In Vitro Prediction Criteria to Assess the Potential of a New Molecular Entity to Inhibit Organic Anion Transporting Polypeptide 1B1
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DOI：
10.1002/jcph.723
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发表时间：
2016-07-01
影响因子：
2.9
通讯作者：
Zhang, Lei
中科院分区：
文献类型：
--
作者：
Vaidyanathan, Jayabharathi;Yoshida, Kenta;Zhang, Lei
评价有机阴离子转运多肽（OATP）1B 1介导的药物相互作用（DDI）是药物开发的一个组成部分，并由监管机构推荐。在本研究中，我们基于体外抑制数据比较了各种预测方法和临界标准，以评估新分子实体在体内抑制OATP 1B 1的潜力。从文献和Drugs@FDA（包括107项临床（体内）DDI研究）中获得了OATP 1B 1的11种底物和61种抑制剂的体外（例如，IC 50，f（u，p））和体内（例如，剂量、C-max、曲线下面积变化[AUC]）数据。观察到底物依赖性和IC 50值的变异性。除未结合或总全身浓度（I-max、I-u和I-max）与IC 50的比值外，还使用肝脏入口处的最大未结合抑制剂浓度（I-u、I-in、I-max）估计“R值”，其中R = 1 + I-u、I-in、I-max/IC 50。根据我们的分析，I-max/K-i >= 0.1，R >= 1.04或R >= 1.1似乎适合于减少假阴性（FN）预测。然而，与R >= 1.1相比，I-max/K-i >= 0.1和R >= 1.04导致更高的假阳性（FP）和更低的真阴性（TN）。单独使用R >= 1.1、I-max、I-u/K-i >= 0.02和R >= 1.25，或I-max/K-i >= 0.1和R >= 1.25的组合标准，可合理确定是否需要使用阳性和阴性预测值相似的OATP 1B 1底物进行临床DDI研究。在解释预测结果时，应考虑不同决策标准的FP或FN的可能原因，并需要了解和尽量减少IC 50测定的变异性。
Evaluation of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an integral part of drug development and is recommended by regulatory agencies. In this study we compared various prediction methods and cutoff criteria based on in vitro inhibition data to assess the potential of a new molecular entity to inhibit OATP1B1 in vivo. In vitro (eg, IC50, f(u,p)) and in vivo (eg, dose, C-max, change in area under the curve [AUC]) data for 11 substrates and 61 inhibitors for OATP1B1 were obtained from literature and Drugs@FDA, which include 107 clinical (in vivo) DDI studies. Substrate dependency and variability of IC50 values were noted. In addition to the ratio of unbound or total systemic concentration (I-max,I-u and I-max) to IC50, maximum unbound inhibitor concentration at the inlet to the liver (I-u,I-in,I-max) was used for the estimation of "R value" where R = 1 + I-u,I-in,I-max/IC50. Based on our analyses, I-max/K-i >= 0.1, R >= 1.04, or R >= 1.1 seem to be appropriate for reducing the false-negative (FN) predictions. However, as compared with R >= 1.1, I-max/K-i >= 0.1 and R >= 1.04 resulted in higher false positives (FPs) and lower true negatives (TNs). R >= 1.1,I-max,I-u/K-i >= 0.02, and R >= 1.25 alone, or combined criterion of I-max/K-i >= 0.1 and R >= 1.25, were reasonable to determine the need to perform clinical DDI studies with OATP1B1 substrates with similar positive and negative predictive values. Possible reasons of FP or FN from different decision criteria should be considered when interpreting prediction results, and the variability in IC50 determination needs to be understood and minimized.