Formerly of Merck & Co., Inc., Kenilworth, New Jersey, USA.
Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Clin Transl Sci. 2021 Mar;14(2):599-605. doi: 10.1111/cts.12917. Epub 2020 Nov 24.
Atogepant is a potent, selective, oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics (PKs) of a once-daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double-blind, placebo-controlled phase I trial in healthy participants. Overall safety, hepatic safety, and plasma PK parameters were evaluated. Thirty-four participants aged 23-55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well-tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except one serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were two discontinuations due to AEs, both with atogepant, one considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant is rapidly absorbed (median time to maximum plasma concentration, ~ 2 hours) with an apparent terminal half-life of ~ 11 hours, and no evidence of accumulation after once-daily dosing. Overall, atogepant at a high oral dose is safe and well-tolerated in healthy participants with no clinically meaningful elevations in ALT.
阿替戈泮是一种有效的、选择性的、口服降钙素基因相关肽（CGRP）受体拮抗剂，目前正在开发用于偏头痛预防。阿替戈泮的化学结构与以前的 CGRP 受体拮抗剂不同，后者在临床试验中与血清丙氨酸氨基转移酶（ALT）升高有关。在这里，我们报告了一项在健康参与者中进行的为期 28 天的、每日一次、超治疗剂量（170mg）的阿替戈泮的安全性、耐受性和药代动力学（PK）的随机、双盲、安慰剂对照 I 期临床试验结果。评估了总体安全性、肝安全性和血浆 PK 参数。34 名年龄在 23-55 岁的参与者入组；28 名（82.4%）按照方案完成了研究。连续 28 天每天服用 170mg 阿替戈泮通常耐受性良好。阿替戈泮组（87.0%）和安慰剂组（72.7%）报告的所有不良事件（AE）均为轻度，除了一起因自行车事故导致的蛛网膜下腔出血的严重 AE 外，均不认为与治疗有关。有两例因 AE 而停药，均与阿替戈泮有关，其中一例可能与治疗有关。在 28 天的治疗期间，没有接受阿替戈泮治疗的参与者的 ALT 升高超过正常上限的 1.5 倍。阿替戈泮与安慰剂组的血清 ALT 水平从基线的变化无差异。阿替戈泮的吸收迅速（中位达峰时间约为 2 小时），表观终末半衰期约为 11 小时，每日一次给药后无蓄积证据。总的来说，高口服剂量的阿替戈泮在健康参与者中是安全且耐受良好的，ALT 无临床意义升高。
