代谢物对基于细胞色素P450抑制的药物相互作用的影响：创新与质量联盟代谢物组药物代谢领导小组的学术成果
Contribution of metabolites to P450 inhibition-based drug-drug interactions: scholarship from the drug metabolism leadership group of the innovation and quality consortium metabolite group.
作者信息
Yu Hongbin, Balani Suresh K, Chen Weichao, Cui Donghui, He Ling, Humphreys W Griffith, Mao Jialin, Lai W George, Lee Anthony J, Lim Heng-Keang, MacLauchlin Christopher, Prakash Chandra, Surapaneni Sekhar, Tse Susanna, Upthagrove Alana, Walsky Robert L, Wen Bo, Zeng Zhaopie
机构信息
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (H.Y.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (S.K.B.); Vertex Pharmaceuticals, San Diego, California (W.C.); Merck Research Laboratories, West Point, Pennsylvania (D.C.); Daiichi Sankyo, Inc. Edison, New Jersey (L.H.); Bristol-Myers Squibb, Princeton, New Jersey (W.G.H.); Genentech, South San Francisco, California (J.M.); Eisai Pharmaceuticals, Andover, Massachusetts (W.G.L.); AbbVie, North Chicago, Illinois (A.J.L.); Janssen Research and Development, Spring House, Pennsylvania (H.-K.L.); GlaxoSmithKline, Research Triangle Park, North Carolina (C.M.); Biogen Idec, Cambridge, Massachusetts (C.P.); Celgene Corporation, Summit, New Jersey (S.S.); Pfizer Inc., Groton, Connecticut (S.T.); Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (A.U.); AstraZeneca, Waltham, Massachusetts (R.L.W.); Department of Drug Metabolism and Pharmacokinetics, Roche Palo Alto, Palo Alto, California (B.W.); and Sanofi, Bridgewater, New Jersey (Z.Z.)
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (H.Y.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (S.K.B.); Vertex Pharmaceuticals, San Diego, California (W.C.); Merck Research Laboratories, West Point, Pennsylvania (D.C.); Daiichi Sankyo, Inc. Edison, New Jersey (L.H.); Bristol-Myers Squibb, Princeton, New Jersey (W.G.H.); Genentech, South San Francisco, California (J.M.); Eisai Pharmaceuticals, Andover, Massachusetts (W.G.L.); AbbVie, North Chicago, Illinois (A.J.L.); Janssen Research and Development, Spring House, Pennsylvania (H.-K.L.); GlaxoSmithKline, Research Triangle Park, North Carolina (C.M.); Biogen Idec, Cambridge, Massachusetts (C.P.); Celgene Corporation, Summit, New Jersey (S.S.); Pfizer Inc., Groton, Connecticut (S.T.); Novartis Pharmaceuticals Corporation, East Hanover, New Jersey (A.U.); AstraZeneca, Waltham, Massachusetts (R.L.W.); Department of Drug Metabolism and Pharmacokinetics, Roche Palo Alto, Palo Alto, California (B.W.); and Sanofi, Bridgewater, New Jersey (Z.Z.).
出版信息
Drug Metab Dispos. 2015 Apr;43(4):620-30. doi: 10.1124/dmd.114.059345. Epub 2015 Feb 5.
Recent European Medicines Agency (final) and US Food and Drug Administration (draft) drug interaction guidances proposed that human circulating metabolites should be investigated in vitro for their drug-drug interaction (DDI) potential if present at ≥ 25% of the parent area under the time-concentration curve (AUC) (US Food and Drug Administration) or ≥ 25% of the parent and ≥ 10% of the total drug-related AUC (European Medicines Agency). To examine the application of these regulatory recommendations, a group of scientists, representing 18 pharmaceutical companies of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted a scholarship to assess the risk of contributions by metabolites to cytochrome P450 (P450) inhibition-based DDIs. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of the 137 most frequently prescribed drugs, defined structural alerts associated with P450 inhibition/inactivation by metabolites, and analyzed current approaches to trigger in vitro DDI studies for metabolites. The group concluded that the risk of P450 inhibition caused by a metabolite alone is low. Only metabolites from 5 of 137 drugs were likely the sole contributor to the in vivo P450 inhibition-based DDIs. Two recommendations were provided when assessing the need to conduct in vitro P450 inhibition studies for metabolites: 1) consider structural alerts that suggest P450 inhibition potential, and 2) use multiple approaches (e.g., a metabolite cut-off value of 100% of the parent AUC and the R(met) strategy) to predict P450 inhibition-based DDIs caused by metabolites in the clinic.
欧洲药品管理局（最终版）和美国食品药品监督管理局（草案）近期发布的药物相互作用指南提出，如果人体循环代谢物在时间-浓度曲线下面积（AUC）中占母体的比例≥25%（美国食品药品监督管理局），或占母体的比例≥25%且占总药物相关AUC的比例≥10%（欧洲药品管理局），则应在体外研究其药物相互作用（DDI）潜力。为检验这些监管建议的适用性，来自创新与质量联盟药物代谢领导小组的18家制药公司的一组科学家开展了一项研究，以评估代谢物对基于细胞色素P450（P450）抑制的药物相互作用产生影响的风险。该小组基于文献数据和对137种最常用处方药的分析，评估了代谢物作为药物相互作用唯一促成因素的风险，确定了与代谢物抑制/灭活P450相关的结构警示，并分析了触发代谢物体外药物相互作用研究的现有方法。该小组得出结论，仅由代谢物引起P450抑制的风险较低。在137种药物中，只有5种药物的代谢物可能是体内基于P450抑制的药物相互作用的唯一促成因素。在评估是否需要对代谢物进行体外P450抑制研究时，提出了两条建议：1）考虑提示P450抑制潜力的结构警示；2）使用多种方法（例如，代谢物截断值为母体AUC的100%和R(met)策略）来预测临床中由代谢物引起的基于P450抑制的药物相互作用。
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