Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Department of Neurosurgery, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
J Headache Pain. 2024 Aug 28;25(1):141. doi: 10.1186/s10194-024-01846-8.
Orally administered second-generation gepants are effective for the treatment of migraine. The intranasal administration of the third-generation gepant zavegepant might have additional benefits including a rapid onset of action, but it is not clear yet to which extent this has clinical relevance.
We examined the effect of zavegepant on the relaxations induced by calcitonin gene-related peptide (CGRP) in human isolated middle meningeal arteries. Furthermore, we connected the pharmacodynamics and pharmacokinetics of gepants by combining data from clinical and basic research.
We showed that 10 nM zavegepant potently antagonized the functional response to CGRP. We also showed that all gepants are effective at inhibiting functional responses to CGRP at their therapeutic plasma concentrations.
The relatively low predicted potency of zavegepant to inhibit CGRP-induced relaxation at therapeutic systemic plasma concentrations may point to the relevance of local delivery to the trigeminovascular system through intranasal administration. This approach may have additional benefits for various groups of patients, including overweight patients.
口服第二代 gepants 对偏头痛的治疗有效。第三代 gepant 那拉曲坦经鼻给药可能具有额外的益处，包括起效更快，但目前尚不清楚这在多大程度上具有临床相关性。
我们研究了那拉曲坦对人离体脑膜中动脉诱导松弛的作用。此外，我们通过将临床和基础研究的数据相结合，来研究 gepants 的药效动力学和药代动力学。
我们表明，10 nM 的那拉曲坦能够强烈拮抗 CGRP 的功能反应。我们还表明，所有 gepants 在其治疗性血浆浓度下都能有效抑制 CGRP 诱导的功能反应。
那拉曲坦在治疗性全身血浆浓度下抑制 CGRP 诱导的松弛的预测效力相对较低，这可能表明通过经鼻给药向三叉血管系统局部给药的相关性。这种方法可能对包括超重患者在内的各种患者群体有额外的益处。
