PDF(Pubmed)
Abstract：
Zavegepant is a novel gepant administered as a nasal spray approved in the United States at a 10 mg dose for the acute treatment of migraine with or without aura in adults. The cardiovascular safety of zavegepant nasal spray was assessed in both single-ascending dose (SAD) and multiple-ascending dose (MAD) studies in healthy participants. The SAD study included 72 participants (54 active/18 placebo) who received 0.1-40 mg zavegepant or placebo. The MAD study included 72 participants (56 active/16 placebo) who received 5-40 mg zavegepant or placebo for 1-14 days. Plasma zavegepant pharmacokinetics and electrocardiographic (ECG) parameters (Fridericia-corrected QT interval [QTcF], heart rate, PR interval, ventricular depolarization [QRS], T-wave morphology, and U-wave presence) were analyzed pre- and post-zavegepant administration. Using pooled data from the SAD and MAD studies, the relationship between time-matched plasma zavegepant concentrations and QTc interval was assessed using a linear mixed-effects model to evaluate the potential for QTc interval prolongation. Results showed that single and multiple doses of zavegepant had no significant impact on ECG parameters versus placebo, and there was no concentration-dependent effect on QTcF interval. The estimated slope of the plasma zavegepant concentration-QTcF model was -0.053 ms per ng/mL with a 90% confidence interval of -0.0955 to -0.0110 (p = 0.0415), which is not considered clinically meaningful. At doses up to four times the recommended daily dose, zavegepant does not prolong the QT interval to any clinically relevant extent.
摘要：
Zavegepant是一种新型gepant，在美国以10mg剂量批准的鼻喷雾剂，用于成人有或没有先兆的偏头痛的急性治疗。在健康参与者的单次递增剂量（SAD）和多次递增剂量（MAD）研究中评估了zavegepant鼻喷雾剂的心血管安全性。SAD研究包括72名参与者（54名活跃/18名安慰剂），他们接受了0.1-40mgzavegepant或安慰剂。MAD研究包括72名参与者（56名活跃/16名安慰剂），他们接受5-40mgzavegepant或安慰剂1-14天。血浆zavegepant药代动力学和心电图（ECG）参数（Fridericia校正的QT间期[QTcF]，心率,PR间隔,心室去极化[QRS]，T波形态,和U波存在）在zavegepant给药前后进行分析。使用来自SAD和MAD研究的汇总数据，使用线性混合效应模型评估了时间匹配的血浆zavegepant浓度与QTc间期之间的关系,以评估QTc间期延长的可能性.结果表明，与安慰剂相比，单剂量和多剂量的zavegepant对ECG参数没有显着影响，对QTcF间期无浓度依赖性影响。血浆zavegepant浓度-QTcF模型的估计斜率为-0.053ms/ng/mL，90％置信区间为-0.0955至-0.0110（p=0.0415），这在临床上没有意义。剂量高达推荐每日剂量的四倍，zavegepant不会将QT间期延长至任何临床相关程度。
