RT Journal Article
SR Electronic
T1 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
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.081927
DO 10.1124/dmd.118.081927
A1 Jane R Kenny
A1 Diane Ramsden
A1 David B Buckley
A1 Shannon Dallas
A1 Conrad Fung
A1 Michael Mohutsky
A1 Heidi J Einolf
A1 Liangfu Chen
A1 Joshua G Dekeyser
A1 Maria Fitzgerald
A1 Theunis C Goosen
A1 Y Amy Siu
A1 Robert L Walsky
A1 George Zhang
A1 Donald Tweedie
A1 Niresh Hariparsad
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/06/29/dmd.118.081927.abstract
AB 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 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, 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. (a) CYP 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) Two-fold induction, with concentration dependence, 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 o ≥ 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 o ≥10-fold. (f) Inclusion of a negative control adds no value beyond that of the vehicle control