The nasty surprise of a complex drug-drug interaction.

In vitro investigation of pharmacokinetic drug-drug interactions (DDIs) has officially been part of the regulatory pathway for new drugs in the USA since the publication of an FDA guidance on the subject in 1997. The field has continued to evolve, driven by preclinical and clinical experience, improved understanding of the molecular basis of DDIs, technological advances, and a continuous dialogue between the FDA and pharmaceutical industry scientists. Some striking DDIs involve multiple molecular species and targets; their mechanisms and magnitude would have been difficult or impossible to predict with available in vitro tools. This article focuses on one such example. Copyright 2010 Elsevier Ltd. All rights reserved.