Transporter-mediated drug-drug interactions: regulatory guidelines, in vitro and in vivo methodologies and translation, special populations, and the blood-brain barrier

Abstract

This review, part of a special issue on drug-drug interactions (DDIs) spearheaded by the International Society for the Study of Xenobiotics (ISSX) New Investigators, explores the critical role of drug transporters in absorption, disposition, and clearance in the context of DDIs. Over the past two decades, significant advances have been made in understanding the clinical relevance of these transporters. Current knowledge on key uptake and efflux transporters that affect drug disposition and development is summarized. Regulatory guidelines from the FDA, EMA, and PMDA that inform the evaluation of potential transporter-mediated DDIs are discussed in detail. Methodologies for preclinical and clinical testing to assess potential DDIs are reviewed, with an emphasis on the utility of physiologically based pharmacokinetic (PBPK) modeling. This includes the application of relative abundance and expression factors to predict human pharmacokinetics (PK) using preclinical data, integrating the latest regulatory guidelines. Considerations for assessing transporter-mediated DDIs in special populations, including pediatric, hepatic, and renal impairment groups, are provided. Additionally, the impact of transporters at the blood-brain barrier (BBB) on the disposition of CNS-related drugs is explored. Enhancing the understanding of drug transporters and their role in drug disposition and toxicity can improve efficacy and reduce adverse effects. Continued research is essential to bridge remaining gaps in knowledge, particularly in comparison with cytochrome P450 (CYP) enzymes.

Keywords:

• Drug transporters
• drug-drug interactions (DDI)
• blood-brain barrier (BBB)
• biomarkers; physiologically-based pharmacokinetic model (PBPK)
• in vitro to in vivo extrapolation (IVIVE)
• clearance; pharmacokinetics (PK)
• genetic variation
• precision medicine

Disclosure statement

Laura Russell is an employee of AbbVie Inc. and may own AbbVie stock. Benjamin Maldonato is an employee of Revolution Medicines, Inc. and may own Revolution Medicines, Inc. stock. Jaydeep Yadav, Ana Vergara, and Erick Villavicencioare employees of Merck & Co., Inc., and may own Merck & Co., Inc. stock. Huan-Chieh Chien & Ling Zou are employees of Amgen Inc. and may own Amgen stock. AbbVie Inc., Revolution Medicines Inc., Merck & Co. Inc., and Amgen Inc. did not sponsor this study. This manuscript is the product of members from the International Society for the Study of Xenobiotics (ISSX) New Investigators Group, which supports the scientific and professional development of student and early career ISSX members through scientific engagement and collaboration.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.