DMPK and Clinical Pharmacology, Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA, 01752, USA.
Pharm Res. 2022 May;39(5):837-850. doi: 10.1007/s11095-022-03267-1. Epub 2022 Apr 28.
Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT agonist activity currently in clinical development for the treatment of schizophrenia. The objectives of the current study were to characterize the in vitro ADME properties, preclinical PK, and to evaluate the DDI potential of ulotaront and its major metabolite SEP-383103.
Solubility, permeability, plasma protein binding, CYP inhibition and induction, transporter inhibition and uptake studies were conducted in vitro. Phenotyping studies were conducted using recombinant human CYPs and FMOs, human liver microsomes and human liver homogenates. Preclinical plasma and brain pharmacokinetics were determined after a single intraperitoneal, intravenous, and oral administration of ulotaront.
Ulotaront is a compound of high solubility, high permeability, and low binding to plasma proteins. Ulotaront metabolism is mediated via both NADPH-dependent and NADPH-independent pathways, with CYP2D6 as the major metabolizing enzyme. Ulotaront is an inducer of CYP2B6, and an inhibitor of CYP2D6, OCT1 and OCT2, while SEP-383103 is neither a CYP inducer nor a potent inhibitor of CYPs and human transporters. Ulotaront exhibits rapid absorption, greater than 70% bioavailability, approximately 3.5 L/kg volume of distribution, 1.5-4 h half-life, 12-43 ml/min/kg clearance, and good penetration across the blood-brain barrier in preclinical species.
Ulotaront has been designated as a BCS1 compound by US FDA. The ability of ulotaront to penetrate the blood-brain barrier for CNS targeting has been demonstrated in mice and rats. The potential for ulotaront and SEP-383103 to act as perpetrators of CYP and transporter-mediated DDIs is predicted to be remote.
Ulotaront（SEP-363856）是一种正在临床开发用于治疗精神分裂症的 TAAR1 激动剂，具有 5-HT 激动剂活性。本研究的目的是表征 ulotaront 及其主要代谢物 SEP-383103 的体外 ADME 特性、临床前 PK，并评估其潜在的药物相互作用。
在体外进行溶解度、渗透性、血浆蛋白结合、CYP 抑制和诱导、转运体抑制和摄取研究。使用重组人 CYP 和 FMO、人肝微粒体和人肝匀浆进行表型研究。单次腹腔内、静脉内和口服给予 ulotaront 后，测定其临床前血浆和脑药代动力学。
Ulotaront 是一种高溶解度、高渗透性、低血浆蛋白结合的化合物。Ulotaront 代谢通过 NADPH 依赖和非依赖途径介导，CYP2D6 为主要代谢酶。Ulotaront 是 CYP2B6 的诱导剂，也是 CYP2D6、OCT1 和 OCT2 的抑制剂，而 SEP-383103 既不是 CYP 诱导剂，也不是 CYP 和人转运体的强效抑制剂。Ulotaront 吸收迅速，生物利用度大于 70%，分布容积约为 3.5 L/kg，半衰期为 1.5-4 h，清除率为 12-43 ml/min/kg，在临床前动物中具有良好的血脑屏障穿透性。
Ulotaront 已被美国 FDA 指定为 BCS1 类化合物。在小鼠和大鼠中已证明 ulotaront 穿透血脑屏障用于中枢神经系统靶向的能力。预计 ulotaront 和 SEP-383103 作为 CYP 和转运体介导的药物相互作用的促成剂的可能性较小。
