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

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 ECF concentrations of serotonin in rats, using microdialysis. While fluoxetine, a selective serotonin reuptake inhibitor, increased the serotonin ECF concentration by 2 - fold, 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 BBB. Across multiple Phase I/II clinical studies with EPAC, 4 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. SIGNIFICANCE STATEMENT: Current preclinical microdialysis data as well as the CNS penetration data in rats suggest that serotonin syndrome is unlikely following treatment with either epacadostat alone or with combination with MAOIs such as linezolid.

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Cat.No. Product Name Information Publications Customer Product Validation
S7910 Epacadostat (INCB024360) Epacadostat (INCB024360) is a potent and selective indoleamine 2,3-dioxygenase (IDO1) inhibitor with IC50 of 10 nM and displays high selectivity over other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). (12) (3)

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