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 InformationSupplementary information accompanies this paper on the Clinical Pharmacology & Therapeutics website (www.cpt-journal.com).
|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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