Predicting drug-drug interactions: an FDA perspective.
Pharmacokinetic drug interactions can lead to serious adverse events, and the evaluation of a new molecular entity's drug-drug interaction potential is an integral part of drug development and regulatory review prior to its market approval. Alteration of enzyme and/or transporter activities involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by other concomitant drugs may lead to a change in exposure leading to altered response (safety or efficacy). Over the years, various in vitro methodologies have been developed to predict drug interaction potential in vivo. In vitro study has become a critical first step in the assessment of drug interactions. Well-executed in vitro studies can be used as a screening tool for the need for further in vivo assessment and can provide the basis for the design of subsequent in vivo drug interaction studies. Besides in vitro experiments, in silico modeling and simulation may also assist in the prediction of drug interactions. The recent FDA draft drug interaction guidance highlighted the in vitro models and criteria that may be used to guide further in vivo drug interaction studies and to construct informative labeling. This report summarizes critical elements in the in vitro evaluation of drug interaction potential during drug development and uses a case study to highlight the impact of in vitro information on drug labeling.
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Rm 3188, Bldg 51, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, USA.
Lei
L
Zhang
Yuanchao Derek
YD
Zhang
Ping
P
Zhao
Shiew-Mei
SM
Huang
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003198:Computer Simulation; D004347:Drug Interactions; D005544:Forecasting; D017408:Guidelines as Topic; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010599:Pharmacokinetics; D014481:United States; D014486:United States Food and Drug Administration
D002352:Carrier Proteins; D004364:Pharmaceutical Preparations