Volume 104, Issue 5 p. 836-864
State of the Art

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

Xiaoyan Chu

Corresponding Author

Xiaoyan Chu

Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc, Kenilworth, New Jersey, USA

Xiaoyan Chu ([email protected]) and Lei Zhang ([email protected])Search for more papers by this author
Mingxiang Liao

Mingxiang Liao

Department of Clinical Pharmacology, Clovis Oncology, Inc., Boulder, Colorado, USA

Search for more papers by this author
Hong Shen

Hong Shen

Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, New Jersey, USA

Search for more papers by this author
Kenta Yoshida

Kenta Yoshida

Clinical Pharmacology, Genentech Research and Early Development, South San Francisco, California, USA

Search for more papers by this author
Arik A. Zur

Arik A. Zur

BiolineRX, Modi'in, Israel

Search for more papers by this author
Vikram Arya

Vikram Arya

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

Search for more papers by this author
Aleksandra Galetin

Aleksandra Galetin

Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK

Search for more papers by this author
Kathleen M. Giacomini

Kathleen M. Giacomini

Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, California, USA

Search for more papers by this author
Imad Hanna

Imad Hanna

Pharmacokinetic Sciences, Novartis Institutes for Biomedical Research, East Hanover, New Jersey, USA

Search for more papers by this author
Hiroyuki Kusuhara

Hiroyuki Kusuhara

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Search for more papers by this author
Yurong Lai

Yurong Lai

Drug Metabolism, Gilead Science, Inc., Foster City, California, USA

Search for more papers by this author
David Rodrigues

David Rodrigues

Pharmacokinetics, Dynamics, & Metabolism, Medicine Design, Pfizer Inc., Groton, Connecticut, USA

Search for more papers by this author
Yuichi Sugiyama

Yuichi Sugiyama

Sugiyama Laboratory, RIKEN Baton Zone Program, Cluster for Science, RIKEN, Yokohama, Japan

Search for more papers by this author
Maciej J. Zamek-Gliszczynski

Maciej J. Zamek-Gliszczynski

Quantitative Drug Disposition, GlaxoSmithKline PLC, King of Prussia, Pennsylvania, USA

Search for more papers by this author
Lei Zhang

Corresponding Author

Lei Zhang

Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA

Xiaoyan Chu ([email protected]) and Lei Zhang ([email protected])Search for more papers by this author
on behalf of the International Transporter Consortium

on behalf of the International Transporter Consortium

Search for more papers by this author
First published: 22 October 2018
Citations: 140

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.

Conflict of Interest

The authors declared no competing interests for this work.