Evaluation of models for predicting drug-drug interactions due to induction.
BACKGROUND
Drug-drug interactions caused by induction of metabolizing enzymes, particularly CYP3A, can impact the efficacy and safety of co-administered drugs. It is, therefore, important to understand a new compound's potential for enzyme induction and to understand how to use the induction data generated in vitro to predict potential for drug-drug interactions in vivo.


METHODS
Recent advances in methods for using in vitro data to predict potential for CYP3A induction in vivo are reviewed.


RESULTS
The reader will gain a comprehensive understanding of the advantages and disadvantages of various prediction methods for induction and be able to directly compare different methods using a common in vitro data set.


CONCLUSIONS
The various methods for predicting clinical CYP3A induction from in vitro induction data all have demonstrated utility; it is the authors' opinion that the correlation-based approaches offer as good or better predictivity and have simpler input requirements than more complex approaches. Of the different correlation approaches, the relatively simple unbound C(max)/EC(50) or AUC/EC(50) approaches are the simplest and yet show the best correlation to the observed clinical data. While the approaches discussed herein represent an improvement in our understanding of the predictive value of in vitro induction data, it is important to recognize that there is still room for improvement in quantitative prediction of magnitude of drug interactions due to induction.
Fahmi
Odette A
OA
Pfizer Global Research and Development, Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Eastern Point Road, Groton, CT 06340, USA. odette.a.fahmi@pfizer.com
Ripp
Sharon L
SL
D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000378:metabolism*; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A