Kenny, Jane, Ramsden, Diane, Buckley, David, Dallas, Shannon, Fung, Conrad, Mohutsky, Michael, Einolf, Heidi, Chen, Liangfu, Dekeyser, Joshua, Fitzgerald, Maria, Goosen, Theunis, Siu, Y. Amy, Walsky, Robert, Zhang, George, Tweedie, Donald and Hariparsad, Niresh (2018) Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidances from Regulatory Agencies: Focus on CYP3A4 mRNA in vitro response thresholds, variability, and clinical relevance. Drug Metabolism and Disposition, 46 (9). pp. 1285-1303. ISSN 0090-95561521-009X

Abstract

Here the IQ 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/EC50 data for prototypical CYP3A4 inducers were compiled from many human hepatocyte donors, repeated over time, in different laboratories. Clinical CYP3A induction and in vitro data were gathered for 51 compounds, 16 of which were proprietary from IQ member companies. A large degree of variability was observed in both the clinical and in vitro induction responses gathered, yet analysis confirmed in vitro data are able to predict clinical induction risk. Following extensive examination of this large dataset, the following recommendations are proposed:
• CYP induction should continue to be evaluated in three separate human donors in vitro.
• 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.
• Two-fold induction, with concentration dependence, is an acceptable threshold for positive identification of in vitro CYP3A4 mRNA induction.
• 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.
• If qualifying a compound as negative for CYP3A4 mRNA induction, the magnitude of maximal rifampicin response in that donor should be ≥10-fold.
• Inclusion of a negative control adds no value beyond that of the vehicle control.

Item Type:	Article
Date Deposited:	16 Oct 2018 00:45
Last Modified:	16 Oct 2018 00:45
URI:	https://oak.novartis.com/id/eprint/36104