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Predicting Drug–Drug Interactions: An FDA Perspective

  • Regulatory Note
  • Theme: Towards Integrated ADME Prediction: Past, Present, and Future Directions
  • Published:
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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.

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Fig. 1

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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Authors and Affiliations

  1. 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 Zhang, Yuanchao (Derek) Zhang, Ping Zhao & Shiew-Mei Huang

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  1. Lei Zhang
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  2. Yuanchao (Derek) Zhang
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  3. Ping Zhao
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  4. Shiew-Mei Huang
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Correspondence to Shiew-Mei Huang.

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Guest Editors: Lawrence X. Yu, Steven C. Sutton, and Michael B. Bolger

The opinions contained in this paper do not necessarily reflect the official views of the FDA.

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Zhang, L., Zhang, Y.(., Zhao, P. et al. Predicting Drug–Drug Interactions: An FDA Perspective. AAPS J 11, 300–306 (2009). https://doi.org/10.1208/s12248-009-9106-3

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