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

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Effects of Epacadostat on Brain Extracellular Fluid Concentrations of Serotonin—An Intracerebral Microdialysis Study in Sprague-Dawley Rats 1521-009X/47/7/710–714$35.00 https://doi.org/10.1124/dmd.118.084053 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 47:710–714, July 2019 Copyright ª 2019 by The American Society for Pharmacology and Experimental Therapeutics Short Communication Effects of Epacadostat on Brain Extracellular Fluid Concentrations of Serotonin—an Intracerebral Microdialysis Study in Sprague-Dawley Rats Received August 22, 2018; accepted April 19, 2019 ABSTRACT Epacadostat (EPAC) is an indoleamine 2,3-dioxygenase 1 (IDO1) in- of fluoxetine with linezolid (a positive control used in the study) resulted hibitor that has been examined in multiple clinical trials. The substrate in a 9-fold increase. Neither EPAC monotherapy nor combination with for IDO1 is tryptophan and there is a theoretical concern that inhibition linezolid had any effect on serotonin concentration. In addition, EPAC Downloaded from of IDO1 may increase the concentrations of tryptophan and sub- was shown to have poor penetration across the rat blood-brain barrier. sequently serotonin, potentially leading to serotonin syndrome (SS). Across multiple phase I/II clinical studies with EPAC, four SS-like The objective of this study was to evaluate the effect of EPAC, either episodes were observed out of 2490 subjects, but none of the alone or with linezolid, a monoamine oxidase inhibitor (MAOI), on brain incidences were confirmed as a true case of SS. These data suggest extracellular fluid (ECF) concentrations of serotonin in rats, using that EPAC is unlikely to cause SS following either monotherapy or in microdialysis. While fluoxetine, a selective serotonin reuptake inhibitor, combination with MAOIs. Thus, the exclusion of MAOI from clinical dmd.aspetjournals.org increased the serotonin ECF concentration by 2-fold, the combination studies with EPAC has been lifted. Introduction theoretical concern is raised that inhibition of IDO1 may increase the Serotonin syndrome (SS) is an adverse, toxic drug reaction caused concentrations of serotonin in the brain by affecting the catabolic by excessive serotonergic activity attributable to increased serotonin pathway of tryptophan either systemically or locally in the brain. Given concentrations in the central nervous system (CNS), and is potentially the potential severity of serotonin toxicity clinically, several studies were at ASPET Journals on October 5, 2021 life threatening (Bijl, 2004). Given the importance of serotonin in the employed. The goals of these investigations were to 1) determine CNS, the synthesis, transport, as well as metabolism of this neurotrans- whether EPAC can cross the rat BBB to have a local effect on the mitter is well regulated by a mechanism involving a bidirectional tryptophan metabolism; 2) examine whether oral administration of communication system between the CNS and the gastrointestinal tract EPAC can increase brain serotonin levels in rats using microdialysis (O’Mahony et al., 2015). Serotonin is synthesized from the essential model; and 3) review the incidence of SS in patients given EPAC. amino acid tryptophan through supplementation in the diet. Tryptophan While SS typically occurs following administration of two or more is first converted to 5-hydroxytryptophan and then to serotonin. This drugs that enhance serotonin concentrations, it can be induced by an process can take place both in the peripheral tissues and also in the brain. overdose of a single agent (Boyer and Shannon, 2005). Therefore, single The majority of serotonin is located in the gut; however, it does not cross agents and combinations were used in these studies to demonstrate SS the blood-brain barrier (BBB). Instead, serotonin in the brain is synthesized in this rat microdialysis model. Linezolid was the first synthetic from circulating tryptophan, which can cross the BBB via large neutral oxazolidinone antimicrobial agent proven to be effective against amino acid transporters (Wurtman et al., 1980). Thus, a drug that increases nosocomial and community-acquired pneumonias and skin infections tryptophan either locally in the CNS or systemically could potentially (Taylor et al., 2006). Linezolid inhibits monoamine oxidase A, which is impact serotonin levels in the brain (Wurtman et al., 1980). responsible for the metabolism of serotonin in the brain. High concentra- Tryptophan has dual metabolic pathways, with the kynurenine tions of serotonin can build up in the brain following monoamine oxidase pathway accounting for approximately 95% and the serotonin pathway inhibitor dosing, especially when combined with other agents such as accounting for 5% of tryptophan catabolism (Prendergast et al., 2017). fluoxetine, which thus could increase intracerebral serotonin concen- Epacadostat (EPAC) (Fig. 1A) is an inhibitor of the enzyme indoleamine trations and cause toxicity (Patel and Galarneau, 2016). Fluoxetine is 2,3-dioxygenase 1 (IDO1) (Liu et al., 2010; Yue et al., 2017), which has a selective serotonin reuptake inhibitor (SSRI), which by definition been examined in multiple clinical trials in combination with checkpoint inhibits the reuptake of the extracellular serotonin by the presynaptic modulators for immune-oncology diseases. IDO1 is a heme-containing neurons, resulting in accumulation of serotonin within the presynaptic enzyme that acts as the rate-limiting step in the breakdown of tryptophan cleft (Cooper and Sejnowski, 2013). Both fluoxetine and its metabolite along the kynurenine pathways (Oxenkrug, 2010) (Fig. 2). Therefore, a norfluoxetine have longer half-lives than other SSRIs, which is problem- atic from a drug interaction standpoint since it can precipitate SS even if All authors are employees and stock holders of Incyte Corporation. discontinued as early as 5 weeks prior to another serotonergic agent being https://doi.org/10.1124/dmd.118.084053. introduced (Boyer and Shannon, 2005; Patel and Galarneau, 2016). ABBREVIATIONS: BBB, blood-brain barrier; CNS, central nervous system; CSF, cerebrospinal fluid; CTCAE v4.0, common terminology criteria for adverse events v4.0; ECF, extracellular fluid; EPAC, epacadostat; IDO1, indoleamine 2,3-dioxygenase 1; MAOI, monoamine oxidase inhibitor; SS, serotonin syndrome; SSRI, selective serotonin reuptake inhibitor. 710 Epacadostat Has No Effect on Brain Serotonin Concentration 711 clinic in the majority of the combination therapies. The intravenous bolus and infusion doses were 2 and 2 mg/kg per hour, respectively. EPAC was formulated in 5% dimethylacetamide in saline. The whole brain, cerebrospinal fluid (CSF), and a terminal blood sample were collected at 4 hours postdose. Blood samples were centrifuged to obtain plasma, CSF samples were diluted 2-fold in plasma to minimize adsorption, and the brain tissue was homogenized with water/acetonitrile/formic acid (95/5/0.1, v/v/v). All samples (plasma, CSF, and brain homogenate) were extracted with five volumes of acetonitrile/methanol (90/10, v/v) mixture. Concentration of EPAC in plasma, CSF, and brain were determined by liquid chromatography–tandem mass spectrometry using Turbo Spray ionization with a positive interface on a Sciex API-4000 (Applied Biosystems/MDS SCIEX, Concord, ON, Canada) and multiple reactions monitoring. Microdialysis Studies in Rats and Data Analysis Microdialysis Study. The microdialysis studies in rats were conducted by Intervivo Solutions (Toronto, ON) and detailed information on the experimental setup, sampling, and quantitative determination of neurochemical analytes can be found elsewhere (Cudjoe et al., 2013). Briefly, male Sprague-Dawley rats were divided into four correspondent groups with four rats in each group. Rats were given either EPAC (25 mg/kg, by mouth) alone, linezolid (100 mg/kg, by mouth) with Downloaded from EPAC (25 mg/kg, by mouth), fluoxetine (10 mg/kg, i.p.) alone, or a combination of linezolid (100 mg/kg, by mouth) plus fluoxetine (10 mg/kg, i.p.). All formulations by mouth were prepared in 0.5% methylcellulose while fluoxetine was formulated in 0.9% sodium chloride solution. A microdialysis probe was implanted into the right striatum and a catheter was placed in the femoral artery of each rat. The microdialysis probe was perfused at 1 ml/min with artificial CSF and dialysate was collected over 40-minute intervals. Dialysate samples were collected prior to dosing (three baseline dmd.aspetjournals.org samples) and over 6 hours after the dose. Plasma concentrations of tryptophan in the Fig. 1. (A) Structure of EPAC (molecular weight = 437 g/mol). (B) Tryptophan vehicle and EPAC (25 mg/kg, by mouth) treatment groups were determine by liquid metabolism pathway. Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting chromatography–tandem mass spectrometry. Liquid chromatography–tandem mass catabolic enzyme in the degradation of the essential amino acid tryptophan along the kynurenine and serotonin pathways. The kynurenine pathway accounts for approximately spectrometry methods were also used to quantify tryptophan, serotonin, and 95% and the serotonin pathway accounts for 5% of tryptophan catabolism. In addition to kynurenine in dialysate samples. Concentrations of each analyte determined in the IDO, tryptophan 2,3-dioxygenase (TDO) is also responsible for the conversion from dialysate samples collected following dosing were compared with those collected at tryptophan to kynurenine. IDO1 is expressed throughout the body and is overexpressed baseline. Since the probes were perfused at a constant flow rate, the relative recovery in multiple tumor types. IDO2 is similar to IDO1 by 41%
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