Effects of Epacadostat on Brain Extracellular Fluid Concentrations of Serotonin-an Intracerebral Microdialysis Study in Sprague-Dawley Rats

Abstract

Epacadostat (EPAC) is an indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor that has been examined in multiple clinical trials. The substrate for IDO1 is tryptophan and there is a theoretical concern that inhibition of IDO1 may increase the concentrations of tryptophan and subsequently serotonin, potentially leading to serotonin syndrome (SS). The objective of this study was to evaluate the effect of EPAC, either alone or with linezolid, a monoamine oxidase inhibitor (MAOI), on brain extracellular fluid (ECF) concentrations of serotonin in rats, using microdialysis. While fluoxetine, a selective serotonin reuptake inhibitor, increased the serotonin ECF concentration by 2-fold, the combination of fluoxetine with linezolid (a positive control used in the study) resulted in a 9-fold increase. Neither EPAC monotherapy nor combination with linezolid had any effect on serotonin concentration. In addition, EPAC was shown to have poor penetration across the rat blood-brain barrier. Across multiple phase I/II clinical studies with EPAC, four SS-like episodes were observed out of 2490 subjects, but none of the incidences were confirmed as a true case of SS. These data suggest that EPAC is unlikely to cause SS following either monotherapy or in combination with MAOIs. Thus, the exclusion of MAOI from clinical studies with EPAC has been lifted.