Abstract：
Drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptides 1B1/1B3 (OATP1B) can be substantial, however, challenges remain for predicting interaction risk. Emerging evidence suggests that endogenous biomarkers, particularly coproporphyrin-I (CP-I), can be used to assess in vivo OATP1B activity. The present work under the International Consortium for Innovation and Quality in Pharmaceutical Development was aimed primarily at assessing CP-I as a biomarker for informing OATP1B DDI risk. Literature and unpublished CP-I data along with pertinent in vitro and clinical DDI information were collected to identify DDIs primarily involving OATP1B inhibition and assess the relationship between OATP1B substrate drug and CP-I exposure changes. Static models to predict changes in exposure of CP-I, as a selective OATP1B substrate, were also evaluated. Significant correlations were observed between CP-I area under the curve ratio (AUCR) or maximum concentration ratio (Cmax R) and AUCR of substrate drugs. In general, the CP-I Cmax R was equal to or greater than the CP-I AUCR. CP-I Cmax R < 1.25 was associated with absence of OATP1B-mediated DDIs (AUCR < 1.25) with no false negative predictions. CP-I Cmax R < 2 was associated with weak OATP1B-mediated DDIs (AUCR < 2). A correlation was identified between CP-I exposure changes and OATP1B1 static DDI predictions. Recommendations for collecting and interpreting CP-I data are discussed, including a decision tree for guiding DDI risk assessment. In conclusion, measurement of CP-I is recommended to inform OATP1B inhibition potential. The current analysis identified changes in CP-I exposure that may be used to prioritize, delay, or replace clinical DDI studies.
摘要：
涉及肝有机阴离子转运多肽1B1/1B3（OATP1B）的药物-药物相互作用（DDI）可以是实质性的，然而,预测互动风险仍然存在挑战。新出现的证据表明，内源性生物标志物，特别是共卟啉-I(CP-I)，可用于评估体内OATP1B活性。国际药物开发创新和质量联盟目前的工作主要旨在评估CP-I作为告知OATP1BDDI风险的生物标志物。收集文献和未发表的CP-I数据以及相关的体外和临床DDI信息，以鉴定主要涉及OATP1B抑制的DDI，并评估OATP1B底物药物与CP-I暴露变化之间的关系。预测CP-I暴露变化的静态模型，作为选择性的OATP1B底物，也进行了评估。在CP-I曲线下面积比（AUCR）或最大浓度比（CmaxR）与底物药物的AUCR之间观察到显着相关性。总的来说,CP-ICmaxR等于或大于CP-IAUCR。CP-ICmaxR<1.25与OATP1B介导的DDI缺失(AUCR<1.25)相关,且无假阴性预测。CP-ICmaxR<2与弱OATP1B介导的DDI（AUCR<2）相关。确定了CP-I暴露变化与OATP1B1静态DDI预测之间的相关性。讨论了收集和解释CP-I数据的建议，包括用于指导DDI风险评估的决策树。总之,建议测量CP-I以告知OATP1B抑制潜力。当前分析确定了CP-I暴露的变化，这些变化可用于确定优先级，延迟或取代临床DDI研究。
