Genentech, South San Francisco, California (J.R.K.); Boehringer Ingelheim, Ridgefield, Connecticut (D.R.); Sekisui-XenoTech LLC, Kansas City, Kansas (D.B.B.); Janssen R&D, Spring House, Pennsylvania (S.D.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H.); Eli Lilly and Company, Indianapolis, Indiana (M.M.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); Amgen Inc., Cambridge, Massachusetts (J.G.D.); Sanofi, Waltham, Massachusetts (M.F.); Pfizer Global Research and Development, Groton, Connecticut (T.C.G.); Eisai, Andover, Massachusetts (Y.A.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.L.W.); Corning Life Sciences, Woburn, Massachusetts (G.Z.); and Merck & Co., Inc., Kenilworth, New Jersey (D.T.)
Genentech, South San Francisco, California (J.R.K.); Boehringer Ingelheim, Ridgefield, Connecticut (D.R.); Sekisui-XenoTech LLC, Kansas City, Kansas (D.B.B.); Janssen R&D, Spring House, Pennsylvania (S.D.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H.); Eli Lilly and Company, Indianapolis, Indiana (M.M.); Novartis, East Hanover, New Jersey (H.J.E.); GlaxoSmithKline, King of Prussia, Pennsylvania (L.C.); Amgen Inc., Cambridge, Massachusetts (J.G.D.); Sanofi, Waltham, Massachusetts (M.F.); Pfizer Global Research and Development, Groton, Connecticut (T.C.G.); Eisai, Andover, Massachusetts (Y.A.S.); EMD Serono R&D Institute, Inc., Billerica, Massachusetts (R.L.W.); Corning Life Sciences, Woburn, Massachusetts (G.Z.); and Merck & Co., Inc., Kenilworth, New Jersey (D.T.).
Drug Metab Dispos. 2018 Sep;46(9):1285-1303. doi: 10.1124/dmd.118.081927. Epub 2018 Jun 29.
The Innovation and Quality Induction Working Group presents an assessment of best practice for data interpretation of in vitro induction, specifically, response thresholds, variability, application of controls, and translation to clinical risk assessment with focus on CYP3A4 mRNA. Single concentration control data and Emax/EC data for prototypical CYP3A4 inducers were compiled from many human hepatocyte donors in different laboratories. Clinical CYP3A induction and in vitro data were gathered for 51 compounds, 16 of which were proprietary. A large degree of variability was observed in both the clinical and in vitro induction responses; however, analysis confirmed in vitro data are able to predict clinical induction risk. Following extensive examination of this large data set, the following recommendations are proposed. a) Cytochrome P450 induction should continue to be evaluated in three separate human donors in vitro. b) In light of empirically divergent responses in rifampicin control and most test inducers, normalization of data to percent positive control appears to be of limited benefit. c) With concentration dependence, 2-fold induction is an acceptable threshold for positive identification of in vitro CYP3A4 mRNA induction. d) To reduce the risk of false positives, in the absence of a concentration-dependent response, induction ≥ 2-fold should be observed in more than one donor to classify a compound as an in vitro inducer. e) If qualifying a compound as negative for CYP3A4 mRNA induction, the magnitude of maximal rifampicin response in that donor should be ≥ 10-fold. f) Inclusion of a negative control adds no value beyond that of the vehicle control.
创新与质量诱导工作组（Innovation and Quality Induction Working Group）对体外诱导数据解释的最佳实践进行了评估，特别是关注 CYP3A4 mRNA 的反应阈值、可变性、对照应用和向临床风险评估的转化。从许多不同实验室的人类肝细胞供体中收集了单个浓度对照数据和原型 CYP3A4 诱导剂的 Emax/EC 数据。为 51 种化合物收集了临床 CYP3A 诱导和体外数据，其中 16 种为专有化合物。在临床和体外诱导反应中都观察到了很大程度的可变性；然而，分析证实，体外数据能够预测临床诱导风险。在对这个大型数据集进行广泛研究后，提出了以下建议。a) 细胞色素 P450 诱导应继续在三个独立的人类供体中进行体外评估。b) 鉴于利福平对照和大多数测试诱导剂的经验分歧反应，将数据归一化为阳性对照的百分比似乎益处有限。c) 由于浓度依赖性，2 倍诱导是体外 CYP3A4 mRNA 诱导阳性识别的可接受阈值。d) 为了降低假阳性的风险，在没有浓度依赖性反应的情况下，在多于一个供体中观察到诱导≥2 倍，以将化合物归类为体外诱导剂。e) 如果将化合物定性为 CYP3A4 mRNA 诱导阴性，该供体中最大利福平反应的幅度应≥10 倍。f) 阴性对照的加入除了载体对照之外没有任何价值。
