Kimura Yasuyuki, Takahata Keisuke, Shimazaki Toshiharu, Kitamura Soichiro, Seki Chie, Ikoma Yoko, Ichise Masanori, Kawamura Kazunori, Yamada Makiko, Zhang Ming-Rong, Higuchi Makoto, Nishino Izumi, Suhara Tetsuya
Department of Functional Brain Imaging, Institute for Quantum Medical Science , National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan.
Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi, 474-8511, Japan.
Eur J Nucl Med Mol Imaging. 2022 Mar;49(4):1127-1135. doi: 10.1007/s00259-021-05571-1. Epub 2021 Oct 15.
Histamine H receptor antagonists and inverse agonists have been extensively developed to treat sleep-wake, neurocognitive, and allied disorders. However, potential adverse effects, including insomnia, hampered the clinical use of these drugs, possibly due to their persistent interaction with the target molecules. The purpose of the present study was to estimate the pharmacokinetics and pharmacodynamics of enerisant, a novel antagonist and inverse agonist for histamine H receptors.
To measure the histamine H receptor occupancy by enerisant, positron emission tomography studies using [C]TASP457, a specific radioligand for histamine H receptors, were performed in 12 healthy men at baseline and at 2 h after oral administration of enerisant hydrochloride. For three of these subjects, two additional scans were performed at 6 and 26 h after the administration. Relationships between the receptor occupancy by enerisant and its dose and plasma concentrations were then analyzed.
Administration of enerisant hydrochloride decreased the radioligand binding in a dose-dependent manner. The estimated receptor occupancy values at 2 h varied as a function of its dose or plasma concentration. The time course of the occupancy showed persistently high levels (> 85%) in the two subjects with higher doses (25 and 12.5 mg). The occupancy was also initially high at 2 h and 6 h with the lower dose of 5 mg, but it decreased to 69.7% at 26 h.
The target engagement of enerisant was demonstrated in the brains of living human subjects. The occupancy of histamine H receptors by enerisant at 2 h can be predicted by applying the plasma concentration of enerisant to Hill's plot. The preliminary time-course investigation showed persistently high brain occupancy with high doses of enerisant despite the decreasing plasma concentration of the drug. Five milligrams or less dose would be appropriate for the treatment for narcolepsy with initially high occupancy allowing for effective treatment of narcolepsy, and then the occupancy level would be expected to decrease to a level to avoid this drug's unwanted side effect of insomnia at night, although further research is warranted to confirm the statement since the expected decrease is based on the finding in one subject.
This study was retrospectively registered with ClinicalTrials.gov (NCT04631276) on November 17, 2020.
组胺H受体拮抗剂和反向激动剂已被广泛开发用于治疗睡眠-觉醒、神经认知及相关疾病。然而，包括失眠在内的潜在不良反应阻碍了这些药物的临床应用，这可能是由于它们与靶分子的持续相互作用所致。本研究的目的是评估enerisant（一种新型组胺H受体拮抗剂和反向激动剂）的药代动力学和药效学。
为了测量enerisant对组胺H受体的占有率，在12名健康男性受试者基线时以及口服盐酸enerisant后2小时，使用[C]TASP457（一种组胺H受体特异性放射性配体）进行正电子发射断层扫描研究。其中3名受试者在给药后6小时和26小时进行了另外两次扫描。然后分析enerisant的受体占有率与其剂量和血浆浓度之间的关系。
口服盐酸enerisant以剂量依赖性方式降低放射性配体结合。2小时时估计的受体占有率值随其剂量或血浆浓度而变化。在两名高剂量（25毫克和12.5毫克）受试者中，占有率的时间进程显示持续高水平（>85%）。低剂量5毫克时，2小时和6小时时占有率最初也较高，但在26小时时降至69.7%。
在活体人类受试者大脑中证实了enerisant与靶点的结合。通过将enerisant的血浆浓度应用于希尔图，可以预测enerisant在2小时时对组胺H受体的占有率。初步的时间进程研究表明，尽管药物血浆浓度降低，但高剂量enerisant时大脑占有率持续较高。5毫克或更低剂量可能适合发作性睡病的治疗，最初占有率较高可有效治疗发作性睡病，然后预计占有率水平会降低到避免该药物夜间失眠不良副作用的水平，不过由于预期的降低是基于一名受试者的发现，因此需要进一步研究来证实这一说法。
本研究于2020年11月17日在ClinicalTrials.gov（NCT04631276）进行回顾性注册。
