Richard Bertz, Mary Donohue, Jennifer Madonia, Rajinder Bhardwaj, Kyle T Matschke, Matt S Anderson, Robert Croop, Jing Liu
{"title":"来自两项1期随机、安慰剂对照试验的健康成人单次和多次递增剂量zavegegpant鼻喷雾剂的安全性、耐受性和药代动力学","authors":"Richard Bertz, Mary Donohue, Jennifer Madonia, Rajinder Bhardwaj, Kyle T Matschke, Matt S Anderson, Robert Croop, Jing Liu","doi":"10.1111/head.15042","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to evaluate the safety and tolerability, and characterize the pharmacokinetic profile, of zavegepant nasal spray in two phase 1 studies.</p><p><strong>Background: </strong>Zavegepant is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist, approved as a nasal spray for the acute treatment of migraine in adults.</p><p><strong>Methods: </strong>Two single-site, phase 1, placebo-controlled, randomized, double-blind studies evaluated the safety, tolerability, and pharmacokinetic profile of single ascending doses (SAD) and multiple ascending doses (MAD) of zavegepant nasal spray in healthy adults. The SAD study was conducted from October 18, 2018, to March 15, 2019, and the MAD study from September 2, 2019, to December 14, 2019. Zavegepant SAD were 0.1-20 mg single sprays and 40 mg as two 20-mg sprays. Zavegepant MAD 5-20 mg single sprays once daily (QD) and three 40-mg QD regimens given as two 20-mg sprays were evaluated.</p><p><strong>Results: </strong>In the SAD study, 72 participants were dosed in nine cohorts, and all participants completed the study. In the MAD study, 72 participants were dosed in six cohorts and 71 (99%) completed the study. In each study, zavegepant was rapidly absorbed, with a median time of maximum observed plasma concentration (T<sub>max</sub>) of 0.54 h after a single 10 mg spray (SAD study). Exposure increased with dose, with no evidence of accumulation after repeated QD dosing. In the SAD study, 14 (26%) zavegepant-treated and three (17%) placebo-treated participants reported at least one treatment-emergent adverse events (TEAE). In the MAD study, 42 (75%) zavegepant-treated participants and 10 (63%) placebo-treated participants reported at least one TEAE. In each study, most TEAEs were mild in severity and resolved spontaneously. There was no relevant effect on electrocardiographic parameters. No signal of drug-induced liver injury was identified.</p><p><strong>Conclusions: </strong>In healthy adults, zavegepant nasal spray was safe and well tolerated at single dose up to 40 mg and in multiple doses up to 40 mg QD. Zavegepant median T<sub>max</sub> was approximately 30 min after a single 10 mg dose nasal spray.</p>","PeriodicalId":12844,"journal":{"name":"Headache","volume":" ","pages":"1331-1343"},"PeriodicalIF":4.0000,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455471/pdf/","citationCount":"0","resultStr":"{\"title\":\"Safety, tolerability, and pharmacokinetics of single and multiple ascending doses of zavegepant nasal spray in healthy adults from two phase 1 randomized, placebo-controlled trials.\",\"authors\":\"Richard Bertz, Mary Donohue, Jennifer Madonia, Rajinder Bhardwaj, Kyle T Matschke, Matt S Anderson, Robert Croop, Jing Liu\",\"doi\":\"10.1111/head.15042\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>This study aimed to evaluate the safety and tolerability, and characterize the pharmacokinetic profile, of zavegepant nasal spray in two phase 1 studies.</p><p><strong>Background: </strong>Zavegepant is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist, approved as a nasal spray for the acute treatment of migraine in adults.</p><p><strong>Methods: </strong>Two single-site, phase 1, placebo-controlled, randomized, double-blind studies evaluated the safety, tolerability, and pharmacokinetic profile of single ascending doses (SAD) and multiple ascending doses (MAD) of zavegepant nasal spray in healthy adults. The SAD study was conducted from October 18, 2018, to March 15, 2019, and the MAD study from September 2, 2019, to December 14, 2019. Zavegepant SAD were 0.1-20 mg single sprays and 40 mg as two 20-mg sprays. Zavegepant MAD 5-20 mg single sprays once daily (QD) and three 40-mg QD regimens given as two 20-mg sprays were evaluated.</p><p><strong>Results: </strong>In the SAD study, 72 participants were dosed in nine cohorts, and all participants completed the study. In the MAD study, 72 participants were dosed in six cohorts and 71 (99%) completed the study. In each study, zavegepant was rapidly absorbed, with a median time of maximum observed plasma concentration (T<sub>max</sub>) of 0.54 h after a single 10 mg spray (SAD study). Exposure increased with dose, with no evidence of accumulation after repeated QD dosing. In the SAD study, 14 (26%) zavegepant-treated and three (17%) placebo-treated participants reported at least one treatment-emergent adverse events (TEAE). In the MAD study, 42 (75%) zavegepant-treated participants and 10 (63%) placebo-treated participants reported at least one TEAE. In each study, most TEAEs were mild in severity and resolved spontaneously. There was no relevant effect on electrocardiographic parameters. No signal of drug-induced liver injury was identified.</p><p><strong>Conclusions: </strong>In healthy adults, zavegepant nasal spray was safe and well tolerated at single dose up to 40 mg and in multiple doses up to 40 mg QD. Zavegepant median T<sub>max</sub> was approximately 30 min after a single 10 mg dose nasal spray.</p>\",\"PeriodicalId\":12844,\"journal\":{\"name\":\"Headache\",\"volume\":\" \",\"pages\":\"1331-1343\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2025-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455471/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Headache\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/head.15042\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/8/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Headache","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/head.15042","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/27 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Safety, tolerability, and pharmacokinetics of single and multiple ascending doses of zavegepant nasal spray in healthy adults from two phase 1 randomized, placebo-controlled trials.
Objective: This study aimed to evaluate the safety and tolerability, and characterize the pharmacokinetic profile, of zavegepant nasal spray in two phase 1 studies.
Background: Zavegepant is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist, approved as a nasal spray for the acute treatment of migraine in adults.
Methods: Two single-site, phase 1, placebo-controlled, randomized, double-blind studies evaluated the safety, tolerability, and pharmacokinetic profile of single ascending doses (SAD) and multiple ascending doses (MAD) of zavegepant nasal spray in healthy adults. The SAD study was conducted from October 18, 2018, to March 15, 2019, and the MAD study from September 2, 2019, to December 14, 2019. Zavegepant SAD were 0.1-20 mg single sprays and 40 mg as two 20-mg sprays. Zavegepant MAD 5-20 mg single sprays once daily (QD) and three 40-mg QD regimens given as two 20-mg sprays were evaluated.
Results: In the SAD study, 72 participants were dosed in nine cohorts, and all participants completed the study. In the MAD study, 72 participants were dosed in six cohorts and 71 (99%) completed the study. In each study, zavegepant was rapidly absorbed, with a median time of maximum observed plasma concentration (Tmax) of 0.54 h after a single 10 mg spray (SAD study). Exposure increased with dose, with no evidence of accumulation after repeated QD dosing. In the SAD study, 14 (26%) zavegepant-treated and three (17%) placebo-treated participants reported at least one treatment-emergent adverse events (TEAE). In the MAD study, 42 (75%) zavegepant-treated participants and 10 (63%) placebo-treated participants reported at least one TEAE. In each study, most TEAEs were mild in severity and resolved spontaneously. There was no relevant effect on electrocardiographic parameters. No signal of drug-induced liver injury was identified.
Conclusions: In healthy adults, zavegepant nasal spray was safe and well tolerated at single dose up to 40 mg and in multiple doses up to 40 mg QD. Zavegepant median Tmax was approximately 30 min after a single 10 mg dose nasal spray.
期刊介绍：
Headache publishes original articles on all aspects of head and face pain including communications on clinical and basic research, diagnosis and management, epidemiology, genetics, and pathophysiology of primary and secondary headaches, cranial neuralgias, and pains referred to the head and face. Monthly issues feature case reports, short communications, review articles, letters to the editor, and news items regarding AHS plus medicolegal and socioeconomic aspects of head pain. This is the official journal of the American Headache Society.
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