The AAPS Journal

, Volume 11, Issue 2, pp 300–306 | Cite as

Predicting Drug–Drug Interactions: An FDA Perspective

  • Lei Zhang
  • Yuanchao (Derek) Zhang
  • Ping Zhao
  • Shiew-Mei Huang
Regulatory Note Theme: Towards Integrated ADME Prediction: Past, Present, and Future Directions

Abstract

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.

Key words

drug development drug–drug interaction new drug application prediction regulatory and guidance 

Abbreviations

ADME

Absorption, distribution, metabolism or excretion

AhR

Aryl hydrocarbon receptor

BCRP

Breast cancer resistance protein

CAR

Constitutive androstane receptor

IND

Investigational new drug

NDA

New drug application

NME

New molecular entity

OAT

Organic anion transporter

OATP

Organic anion transporting polypeptide

OCT

Organic cation transporter

P-gp

P-glycoprotein

UGT

UDP-glucuronosyltransferase

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Copyright information

© American Association of Pharmaceutical Scientists 2009

Authors and Affiliations

  • Lei Zhang
    • 1
  • Yuanchao (Derek) Zhang
    • 1
  • Ping Zhao
    • 1
  • Shiew-Mei Huang
    • 1
  1. 1.Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and ResearchFood and Drug AdministrationSilver SpringUSA

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