Human Pharmacokinetics of XBD173 and Etifoxine Distinguish Their Potential for Pharmacodynamic Effects Mediated by Translocator Protein

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 2022 May 7

PMID 35524344

Authors

David R Owen

Alexandra Phillips

Desmond OConnor

Gabrielle Grey

Lina Aimola

Richard Nicholas

Paul M Matthews

Affiliations

Soon will be listed here.

Abstract

XBD173 and etifoxine are translocator protein (TSPO) ligands that modulate inflammatory responses in preclinical models. Limited human pharmacokinetic data is available for either molecule, and the binding affinity of etifoxine for human TSPO is unknown. To allow for design of human challenge experiments, we derived pharmacokinetic data for orally administered etifoxine (50 mg 3 times daily) and XBD173 (90 mg once daily) and determined the binding affinity of etifoxine for TSPO. For XBD173, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 1.0 nM, which is similar to XBD173 binding affinity. For etifoxine, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 0.31 nM, substantially lower than the K for etifoxine in human brain derived here (7.8 μM, 95% CI 4.5-14.6 μM). We conclude that oral XBD173 dosing at 90 mg once daily will achieve pharmacologically relevant TSPO occupancy. However, the occupancy is too low for TSPO mediated effects after oral dosing of etifoxine at 50 mg 3 times daily.

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Human pharmacokinetics of XBD173 and etifoxine distinguish their potential for pharmacodynamic effects mediated by translocator protein.

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