Sumitomo Pharma America, Inc, Cambridge, Massachusetts, USA.
Pharmacol Res Perspect. 2024 Apr;12(2):e1191. doi: 10.1002/prp2.1191.
Ulotaront (SEP-363856) is a TAAR1 agonist, with 5-HT1A agonist activity, currently in clinical development for the treatment of schizophrenia. In vitro studies indicate ulotaront is an OCT2-specific inhibitor with IC of 1.27 μM. The primary objective of this study is to determine if a single dose of ulotaront affects the PK of metformin, an index substrate of OCT2, in subjects with schizophrenia. In a randomized, single-blind, 2-period crossover study, 25 adults with schizophrenia received a single dose of metformin-HCl 850 mg (approximately 663 mg metformin) with and without coadministration of 100 mg ulotaront. The plasma samples were analyzed by fully validated LC-MS/MS methods. The primary PK endpoints for metformin were AUC, AUC, C, and t. The highest-anticipated clinical dose of ulotaront (100 mg) had no statistically significant effect on the PK of a single dose of metformin based on C and AUC. Geometric least squares mean ratios were 89.98% and 110.63%, respectively, with the 90% confidential interval (CI) for each parameter contained within 80%-125%. Median t was comparable across the treatments. Ulotaront does not act as a perpetrator of OCT2-mediated DDI against metformin. Co-administration of ulotaront is not expected to require dose adjustment of metformin or other drugs cleared by OCT2.
乌洛托隆（SEP-363856）是一种 TAAR1 激动剂，具有 5-HT1A 激动剂活性，目前正在开发用于治疗精神分裂症。体外研究表明，乌洛托隆是一种 OCT2 特异性抑制剂，IC 为 1.27μM。本研究的主要目的是确定单次剂量的乌洛托隆是否会影响精神分裂症患者中 OCT2 指数底物二甲双胍的 PK。在一项随机、单盲、2 期交叉研究中，25 名精神分裂症患者接受了单次剂量的二甲双胍盐酸盐 850mg（约 663mg 二甲双胍），并同时给予 100mg 乌洛托隆。通过完全验证的 LC-MS/MS 方法分析血浆样本。二甲双胍的主要 PK 终点为 AUC、AUC、C 和 t。乌洛托隆的最高预期临床剂量（100mg）对单次剂量的二甲双胍的 PK 没有统计学显著影响，基于 C 和 AUC。几何最小二乘均值比值分别为 89.98%和 110.63%，每个参数的 90%置信区间（CI）均在 80%-125%范围内。两种治疗方法的 t 值中位数相似。乌洛托隆不会对 OCT2 介导的 DDI 产生二甲双胍的作用。乌洛托隆的共同给药预计不需要调整二甲双胍或其他由 OCT2 清除的药物的剂量。
