Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752, USA.
Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI 53704, USA.
J Pharm Biomed Anal. 2022 Jan 5;207:114404. doi: 10.1016/j.jpba.2021.114404. Epub 2021 Oct 6.
Ulotaront (SEP-363856) is a novel non-D2-receptor-binding agent under development for the treatment of patients with schizophrenia. A highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with lower limit of quantitation of 0.0200 ng/mL (i.e. 20.0 pg/mL) was successfully developed and validated for the simultaneous quantitation of ulotaront and its N-desmethyl metabolite (M11A) in human plasma. Plasma samples were extracted by solid phase extraction with Oasis MCX 96-well plate, followed by a reversed phase LC separation coupled with MS/MS detection in positive mode (m/z 184.1 → 135.0 for ulotaront and 170.1 → 135.0 for M11A). Stable isotope-labeled compounds SEP-363856-d and M11A-d were used as internal standards (IS) for corresponding analytes. The validated calibration curve range was 0.0200-20.0 ng/mL for both analytes using a 0.200 mL plasma. Extraction recoveries were found to be 75.7% and 75.1% for ulotaront and IS1, and 82.7% and 83.9% for M11A and IS2, respectively. Frozen plasma samples were confirmed to be stable for up to 730 days at both -20 °C and -70 °C. The validated method has been successfully used to evaluate the pharmacokinetics (PK) of ulotaront and M11A in clinical studies. The application to the first-in-human PK study (single ascending dose) presented in this work demonstrated that ulotaront exhibited near dose proportionality for both C (maximum concentration) and AUC (area under the curve) over the dose range from 5 to 125 mg. M11A was found as a minor metabolite with an exposure of about 2-3% of the parent compound.
乌洛托仑（SEP-363856）是一种新型的非 D2 受体结合剂，正在开发用于治疗精神分裂症患者。成功开发并验证了一种高灵敏度的液相色谱-串联质谱（LC-MS/MS）方法，定量下限为 0.0200ng/mL（即 20.0pg/mL），可同时定量测定人血浆中的乌洛托仑及其 N-去甲基代谢物（M11A）。采用固相萃取法（Oasis MCX 96 孔板）提取血浆样品，然后进行反相 LC 分离，结合 MS/MS 检测，正离子模式（m/z 184.1→135.0 用于乌洛托仑，m/z 170.1→135.0 用于 M11A）。稳定同位素标记化合物 SEP-363856-d 和 M11A-d 被用作相应分析物的内标（IS）。使用 0.200mL 血浆，两种分析物的验证校准曲线范围均为 0.0200-20.0ng/mL。乌洛托仑和 IS1 的提取回收率分别为 75.7%和 75.1%，M11A 和 IS2 的提取回收率分别为 82.7%和 83.9%。冷冻血浆样品在-20°C 和-70°C 下分别可稳定 730 天以上。该验证方法已成功用于临床研究中乌洛托仑和 M11A 的药代动力学（PK）评价。本文介绍的首次人体 PK 研究（单剂量递增）的应用表明，乌洛托仑在 5-125mg 剂量范围内，C（最大浓度）和 AUC（曲线下面积）均表现出接近剂量比例性。M11A 是一种次要代谢物，其暴露量约为母体化合物的 2-3%。
