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,
Mingxiang Liao,
Hong Shen,
Kenta Yoshida,
Arik A. Zur, Vikram Arya,
Aleksandra Galetin,
Kathleen M. Giacomini,
Imad Hanna,
Hiroyuki Kusuhara,
Yurong Lai,
David Rodrigues,
Yuichi Sugiyama,
Maciej J. Zamek-Gliszczynski,
Lei Zhang,
on behalf of the International Transporter Consortium,
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 authorMingxiang Liao
Department of Clinical Pharmacology, Clovis Oncology, Inc., Boulder, Colorado, USA
Search for more papers by this authorHong Shen
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, New Jersey, USA
Search for more papers by this authorKenta Yoshida
Clinical Pharmacology, Genentech Research and Early Development, South San Francisco, California, USA
Search for more papers by this authorVikram 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 authorAleksandra Galetin
Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK
Search for more papers by this authorKathleen 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 authorImad Hanna
Pharmacokinetic Sciences, Novartis Institutes for Biomedical Research, East Hanover, New Jersey, USA
Search for more papers by this authorHiroyuki Kusuhara
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
Search for more papers by this authorYurong Lai
Drug Metabolism, Gilead Science, Inc., Foster City, California, USA
Search for more papers by this authorDavid Rodrigues
Pharmacokinetics, Dynamics, & Metabolism, Medicine Design, Pfizer Inc., Groton, Connecticut, USA
Search for more papers by this authorYuichi Sugiyama
Sugiyama Laboratory, RIKEN Baton Zone Program, Cluster for Science, RIKEN, Yokohama, Japan
Search for more papers by this authorMaciej J. Zamek-Gliszczynski
Quantitative Drug Disposition, GlaxoSmithKline PLC, King of Prussia, Pennsylvania, USA
Search for more papers by this authorCorresponding 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 authoron behalf of the International Transporter Consortium
Search for more papers by this authorXiaoyan Chu,
Mingxiang Liao,
Hong Shen,
Kenta Yoshida,
Arik A. Zur, Vikram Arya,
Aleksandra Galetin,
Kathleen M. Giacomini,
Imad Hanna,
Hiroyuki Kusuhara,
Yurong Lai,
David Rodrigues,
Yuichi Sugiyama,
Maciej J. Zamek-Gliszczynski,
Lei Zhang,
on behalf of the International Transporter Consortium,
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 authorMingxiang Liao
Department of Clinical Pharmacology, Clovis Oncology, Inc., Boulder, Colorado, USA
Search for more papers by this authorHong Shen
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, New Jersey, USA
Search for more papers by this authorKenta Yoshida
Clinical Pharmacology, Genentech Research and Early Development, South San Francisco, California, USA
Search for more papers by this authorVikram 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 authorAleksandra Galetin
Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK
Search for more papers by this authorKathleen 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 authorImad Hanna
Pharmacokinetic Sciences, Novartis Institutes for Biomedical Research, East Hanover, New Jersey, USA
Search for more papers by this authorHiroyuki Kusuhara
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
Search for more papers by this authorYurong Lai
Drug Metabolism, Gilead Science, Inc., Foster City, California, USA
Search for more papers by this authorDavid Rodrigues
Pharmacokinetics, Dynamics, & Metabolism, Medicine Design, Pfizer Inc., Groton, Connecticut, USA
Search for more papers by this authorYuichi Sugiyama
Sugiyama Laboratory, RIKEN Baton Zone Program, Cluster for Science, RIKEN, Yokohama, Japan
Search for more papers by this authorMaciej J. Zamek-Gliszczynski
Quantitative Drug Disposition, GlaxoSmithKline PLC, King of Prussia, Pennsylvania, USA
Search for more papers by this authorCorresponding 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 authoron behalf of the International Transporter Consortium
Search for more papers by this authorAbstract
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.
Supporting Information
Supporting InformationSupplementary information accompanies this paper on the Clinical Pharmacology & Therapeutics website (www.cpt-journal.com).
| Filename | Description |
|---|---|
| cpt1216-sup-0001-FigS1.pdfPDF document, 1.5 MB | Figure S1. Mechanistic challenges on developing endogenous biomarker models for renal transporters. |
| cpt1216-sup-0002-FigS2.pdfPDF document, 1.3 MB | Figure S2. Effect of t1/2 and % inhibition on endogenous biomarker concentration-time profiles. |
| cpt1216-sup-0003-TableS1.docxWord document, 58.2 KB | Table S1. Identification and characterization of potential endogenous biomarkers for several hepatic transporters using animal models. |
| cpt1216-sup-0004-TableS2.docxWord document, 88.6 KB | Table S2. Impact of OATP1B1 and BCRP genetic polymorphisms on rosuvastatin PK. |
| cpt1216-sup-0005-TableS3.docxWord document, 58.2 KB | Table S3. Methods for identification of endogenous biomarkers for drug transporters. |
| cpt1216-sup-0006-Supinfo1.docxWord document, 42.4 KB | Supplementary Materials S1. Additional considerations on recommended methods for interpreting systemic exposure changes in biomarkers with competitive inhibition of transporters. |
| cpt1216-sup-0007-Supinfo2.docxWord document, 23.9 KB | Supplementary Materials S2. Reading List. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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