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Clin Pharmacol Ther. 2018 Nov;104(5):836-864. doi: 10.1002/cpt.1216.

Clinical Probes and Endogenous Biomarkers as Substrates for Transporter Drug-Drug Interaction Evaluation: Perspectives From the International Transporter Consortium.

Author information

1
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc, Kenilworth, New Jersey, USA.
2
Department of Clinical Pharmacology, Clovis Oncology, Inc., Boulder, Colorado, USA.
3
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, New Jersey, USA.
4
Clinical Pharmacology, Genentech Research and Early Development, South San Francisco, California, USA.
5
BiolineRX, Modi'in, Israel.
6
Division of Clinical Pharmacology IV, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
7
Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.
8
Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California, USA.
9
Pharmacokinetic Sciences, Novartis Institutes for Biomedical Research, East Hanover, New Jersey, USA.
10
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
11
Drug Metabolism, Gilead Science, Inc., Foster City, California, USA.
12
Pharmacokinetics, Dynamics, & Metabolism, Medicine Design, Pfizer Inc., Groton, Connecticut, USA.
13
Sugiyama Laboratory, RIKEN Baton Zone Program, Cluster for Science, RIKEN, Yokohama, Japan.
14
Quantitative Drug Disposition, GlaxoSmithKline PLC, King of Prussia, Pennsylvania, USA.
15
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.

Abstract

Drug transporters can govern the absorption, distribution, metabolism, and excretion of substrate drugs and endogenous substances. Investigations to examine their potential impact to pharmacokinetic (PK) drug-drug interactions (DDIs) are an integral part of the risk assessment in drug development. To evaluate a new molecular entity as a potential perpetrator of transporters, use of well characterized and/or clinically relevant probe substrates with good selectivity and sensitivity are critical for robust clinical DDI assessment that could inform DDI management strategy in the product labeling. The availability of endogenous biomarkers to monitor transporter-mediated DDIs in early phases of clinical investigations would greatly benefit downstream clinical plans. This article reviews the state-of-the-art in transporter clinical probe drugs and emerging biomarkers, including current challenges and limitations, delineates methods and workflows to identify and validate novel endogenous biomarkers to support clinical DDI evaluations, and proposes how these probe drugs or biomarkers could be used in drug development.

PMID:
30347454
DOI:
10.1002/cpt.1216

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