Clinical Implications of Altered Drug Transporter Abundance/Function and PBPK Modeling in Specific Populations: An ITC Perspective.
Document Type
Article
Publication Date
9-2022
Identifier
DOI: 10.1002/cpt.2643
Abstract
The role of membrane transporters on pharmacokinetics (PKs), drug-drug interactions (DDIs), pharmacodynamics (PDs), and toxicity of drugs has been broadly recognized. However, our knowledge of modulation of transporter expression and/or function in the diseased patient population or specific populations, such as pediatrics or pregnancy, is still emerging. This white paper highlights recent advances in studying the changes in transporter expression and activity in various diseases (i.e., renal and hepatic impairment and cancer) and some specific populations (i.e., pediatrics and pregnancy) with the focus on clinical implications. Proposed alterations in transporter abundance and/or activity in diseased and specific populations are based on (i) quantitative transporter proteomic data and relative abundance in specific populations vs. healthy adults, (ii) clinical PKs, and emerging transporter biomarker and/or pharmacogenomic data, and (iii) physiologically-based pharmacokinetic modeling and simulation. The potential for altered PK, PD, and toxicity in these populations needs to be considered for drugs and their active metabolites in which transporter-mediated uptake/efflux is a major contributor to their absorption, distribution, and elimination pathways and/or associated DDI risk. In addition to best practices, this white paper discusses current challenges and knowledge gaps to study and quantitatively predict the effects of modulation in transporter activity in these populations, together with the perspectives from the International Transporter Consortium (ITC) on future directions.
Journal Title
Clinical pharmacology and therapeutics
Volume
112
Issue
3
First Page
501
Last Page
526
MeSH Keywords
Adult; Biological Transport; Child; Drug Interactions; Humans; Membrane Transport Proteins; Models, Biological; Proteomics
Keywords
Biological Transport; Drug Interactions; Membrane Transport Proteins; Biological Models; Proteomics
Recommended Citation
Chu X, Prasad B, Neuhoff S, et al. Clinical Implications of Altered Drug Transporter Abundance/Function and PBPK Modeling in Specific Populations: An ITC Perspective. Clin Pharmacol Ther. 2022;112(3):501-526. doi:10.1002/cpt.2643
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