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. 2022 Dec;62(12):1501-1506.
doi: 10.1002/jcph.2119. Epub 2022 Jul 19.

Using Endogenous Biomarkers to Derisk Assessment of Transporter-Mediated Drug-Drug Interactions: A Scientific Perspective

Vikram Arya  1 , Kellie S Reynolds  1 , Xinning Yang  2
Affiliations

Using Endogenous Biomarkers to Derisk Assessment of Transporter-Mediated Drug-Drug Interactions: A Scientific Perspective

Vikram Arya et al. J Clin Pharmacol. 2022 Dec.

Abstract

Comprehensive characterization of transporter mediated drug-drug interactions (DDIs) is important to formulate clinical management strategies and ensure the safe and effective use of concomitantly administered drugs. The potential of a drug to inhibit transporters is predicted by comparing the ratio of the relevant concentration (depending on the transporter) and the half maximum inhibitory concentration to a predefined "cutoff" value. If the ratio is greater than the cutoff value, modeling approaches such as physiologically based pharmacokinetic modeling or a clinical DDI trial may be recommended. Because false-positive (in vitro data suggest the potential for a DDI, whereas no significant DDI is observed in vivo) and false-negative (in vitro data does not suggest the potential for a DDI, whereas significant DDI is observed in vivo) outcomes have been observed, there is interest in exploring additional approaches to facilitate prediction of transporter-mediated DDIs. The idea of assessing changes in the concentration of endogenous biomarkers (which are substrates of clinically relevant transporters) to gain insight on the potential for a drug to inhibit transporter activity has received widespread attention. This brief report describes how endogenous biomarkers may help to expand the DDI assessment toolkit, highlights some current knowledge gaps, and outlines a conceptual framework that may complement the current paradigm of predicting the potential for transporter-mediated DDIs.

Keywords: coproporphyrins; drug-drug interactions; endogenous biomarkers; physiologically based pharmacokinetic (PBPK) modeling; transporters.

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References

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