Departments of Drug Metabolism Pharmacokinetics and Clinical Pharmacology (Y.Z., K.B., S.D., S.Y.), and Clinical Development (J.M.), Incyte Corporation, Wilmington, Delaware
Departments of Drug Metabolism Pharmacokinetics and Clinical Pharmacology (Y.Z., K.B., S.D., S.Y.), and Clinical Development (J.M.), Incyte Corporation, Wilmington, Delaware.
Drug Metab Dispos. 2019 Jul;47(7):710-714. doi: 10.1124/dmd.118.084053. Epub 2019 Apr 22.
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.
依匹卡肽（EPAC）是一种吲哚胺 2,3-双加氧酶 1（IDO1）抑制剂，已在多项临床试验中进行了研究。IDO1 的底物是色氨酸，理论上存在抑制 IDO1 可能会增加色氨酸浓度，从而增加血清素，进而导致血清素综合征（SS）的风险。本研究的目的是使用微透析评估 EPAC（单独使用或与单胺氧化酶抑制剂（MAOI）利奈唑胺联合使用）对大鼠脑细胞外液（ECF）中血清素浓度的影响。氟西汀是一种选择性 5-羟色胺再摄取抑制剂，可将血清素 ECF 浓度增加 2 倍，而氟西汀与利奈唑胺（研究中使用的阳性对照）联合使用可使血清素浓度增加 9 倍。EPAC 单药治疗或与利奈唑胺联合使用均对血清素浓度没有影响。此外，EPAC 在大鼠血脑屏障中的穿透性较差。在 EPAC 的多项 I/II 期临床试验中，在 2490 名受试者中观察到 4 例类似 SS 的发作，但均未确诊为 SS 病例。这些数据表明，EPAC 无论是单独使用还是与 MAOIs 联合使用，都不太可能引起 SS。因此，已取消 EPAC 临床试验中排除 MAOI 的要求。
