How Science Is Driving Regulatory Guidances.

ABSTRACT

This chapter provides regulatory perspectives on how to translate in vitro drug metabolism findings into in vivo drug-drug interaction (DDI) predictions and how this affects the decision of conducting in vivo DDI evaluation. The chapter delineates rationale and analyses that have supported the recommendations in the U.S. Food and Drug Administration (FDA) DDI guidances in terms of in vitro-in vivo extrapolation of cytochrome P450 (CYP) inhibition-mediated DDI potential for investigational new drugs and their metabolites as substrates or inhibitors. The chapter also describes the framework and considerations to assess UDP-glucuronosyltransferase (UGT) inhibition-mediated DDI potential for drugs as substrates or inhibitors. The limitations of decision criteria and further improvements needed are also discussed. Case examples are provided throughout the chapter to illustrate how decision criteria have been utilized to evaluate in vivo DDI potential from in vitro data.