Rajinder Bhardwaj, Julie Collins, Jennifer Madonia, Kyle Matschke, Richard Bertz, Jing Liu
{"title":"zavegepant鼻腔喷雾剂多剂量给药对炔雌醇-左炔诺孕酮单剂量药代动力学的影响。","authors":"Rajinder Bhardwaj, Julie Collins, Jennifer Madonia, Kyle Matschke, Richard Bertz, Jing Liu","doi":"10.1111/head.14863","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>The potential for drug-drug interaction of multiple-dose intranasal zavegepant on the single-dose oral contraceptive ethinyl estradiol and levonorgestrel (EE-LNG) was evaluated.</p><p><strong>Background: </strong>Zavegepant (as a nasal spray) is a calcitonin gene-related peptide receptor antagonist approved in the United States for treatment of acute migraine in adults.</p><p><strong>Methods: </strong>This single-center, Phase 1, open-label, fixed-sequence study included healthy, nonsmoking females (18-45 years old). In treatment Period 1, a single oral dose of EE-LNG 0.02-0.10 mg was administered on Day 1. In treatment Period 2, intranasal zavegepant (20 mg daily; 10 mg per nostril separated by 1 h) was administered on Days 1-5; 1 oral dose of EE-LNG 0.02-0.10 mg was administered immediately after first 10 mg intranasal zavegepant dose on Day 2. Blood samples for EE-LNG concentrations were collected on Day 1, treatment Period 1, and Day 2, treatment Period 2, and zavegepant concentrations on Day 2, treatment Period 2. Noncompartmental pharmacokinetic parameters included maximum observed concentration (C<sub>max</sub>), area under the concentration-time curve (AUC) from Time 0 to last non-zero concentration (AUC<sub>0-t</sub>), and AUC from Time 0 to infinity (AUC<sub>0-inf</sub>). The safety and pharmacokinetic sample sizes were 26 and 23, respectively.</p><p><strong>Results: </strong>Statistical comparisons of pharmacokinetic exposure parameters after co-administration of zavegepant and EE-LNG versus EE-LNG alone showed small, but statistically insignificant, changes in either EE or LNG exposure. EE comparison ratios (90% confidence intervals [CIs]) were 109.9% (105.3%, 114.8%) for AUC<sub>0-inf</sub> and 110.2% (104.6%, 116.1%) for C<sub>max</sub>. LNG comparison ratios (90% CIs) were 107.0% (100.2%, 114.3%) for AUC<sub>0-inf</sub> and 108.8% (99.9%, 118.4%) for C<sub>max</sub>. Frequently reported treatment-emergent adverse events included dysgeusia (n = 25, 96%), throat irritation (n = 11, 42%), headache (n = 10, 39%), nasal discomfort (n = 7, 27%), pharyngeal paresthesia (n = 5, 19%), and nausea (n = 4, 15%).</p><p><strong>Conclusion: </strong>Co-administration of zavegepant nasal spray with a single dose of an oral contraceptive resulted in no clinically meaningful changes (<12% increase) in EE-LNG exposure.</p>","PeriodicalId":12844,"journal":{"name":"Headache","volume":" ","pages":""},"PeriodicalIF":5.4000,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Effects of multiple-dose administration of zavegepant nasal spray on the single-dose pharmacokinetics of ethinyl estradiol-levonorgestrel.\",\"authors\":\"Rajinder Bhardwaj, Julie Collins, Jennifer Madonia, Kyle Matschke, Richard Bertz, Jing Liu\",\"doi\":\"10.1111/head.14863\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>The potential for drug-drug interaction of multiple-dose intranasal zavegepant on the single-dose oral contraceptive ethinyl estradiol and levonorgestrel (EE-LNG) was evaluated.</p><p><strong>Background: </strong>Zavegepant (as a nasal spray) is a calcitonin gene-related peptide receptor antagonist approved in the United States for treatment of acute migraine in adults.</p><p><strong>Methods: </strong>This single-center, Phase 1, open-label, fixed-sequence study included healthy, nonsmoking females (18-45 years old). In treatment Period 1, a single oral dose of EE-LNG 0.02-0.10 mg was administered on Day 1. In treatment Period 2, intranasal zavegepant (20 mg daily; 10 mg per nostril separated by 1 h) was administered on Days 1-5; 1 oral dose of EE-LNG 0.02-0.10 mg was administered immediately after first 10 mg intranasal zavegepant dose on Day 2. Blood samples for EE-LNG concentrations were collected on Day 1, treatment Period 1, and Day 2, treatment Period 2, and zavegepant concentrations on Day 2, treatment Period 2. Noncompartmental pharmacokinetic parameters included maximum observed concentration (C<sub>max</sub>), area under the concentration-time curve (AUC) from Time 0 to last non-zero concentration (AUC<sub>0-t</sub>), and AUC from Time 0 to infinity (AUC<sub>0-inf</sub>). The safety and pharmacokinetic sample sizes were 26 and 23, respectively.</p><p><strong>Results: </strong>Statistical comparisons of pharmacokinetic exposure parameters after co-administration of zavegepant and EE-LNG versus EE-LNG alone showed small, but statistically insignificant, changes in either EE or LNG exposure. EE comparison ratios (90% confidence intervals [CIs]) were 109.9% (105.3%, 114.8%) for AUC<sub>0-inf</sub> and 110.2% (104.6%, 116.1%) for C<sub>max</sub>. LNG comparison ratios (90% CIs) were 107.0% (100.2%, 114.3%) for AUC<sub>0-inf</sub> and 108.8% (99.9%, 118.4%) for C<sub>max</sub>. Frequently reported treatment-emergent adverse events included dysgeusia (n = 25, 96%), throat irritation (n = 11, 42%), headache (n = 10, 39%), nasal discomfort (n = 7, 27%), pharyngeal paresthesia (n = 5, 19%), and nausea (n = 4, 15%).</p><p><strong>Conclusion: </strong>Co-administration of zavegepant nasal spray with a single dose of an oral contraceptive resulted in no clinically meaningful changes (<12% increase) in EE-LNG exposure.</p>\",\"PeriodicalId\":12844,\"journal\":{\"name\":\"Headache\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2024-11-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Headache\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/head.14863\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Headache","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/head.14863","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Effects of multiple-dose administration of zavegepant nasal spray on the single-dose pharmacokinetics of ethinyl estradiol-levonorgestrel.
Objective: The potential for drug-drug interaction of multiple-dose intranasal zavegepant on the single-dose oral contraceptive ethinyl estradiol and levonorgestrel (EE-LNG) was evaluated.
Background: Zavegepant (as a nasal spray) is a calcitonin gene-related peptide receptor antagonist approved in the United States for treatment of acute migraine in adults.
Methods: This single-center, Phase 1, open-label, fixed-sequence study included healthy, nonsmoking females (18-45 years old). In treatment Period 1, a single oral dose of EE-LNG 0.02-0.10 mg was administered on Day 1. In treatment Period 2, intranasal zavegepant (20 mg daily; 10 mg per nostril separated by 1 h) was administered on Days 1-5; 1 oral dose of EE-LNG 0.02-0.10 mg was administered immediately after first 10 mg intranasal zavegepant dose on Day 2. Blood samples for EE-LNG concentrations were collected on Day 1, treatment Period 1, and Day 2, treatment Period 2, and zavegepant concentrations on Day 2, treatment Period 2. Noncompartmental pharmacokinetic parameters included maximum observed concentration (Cmax), area under the concentration-time curve (AUC) from Time 0 to last non-zero concentration (AUC0-t), and AUC from Time 0 to infinity (AUC0-inf). The safety and pharmacokinetic sample sizes were 26 and 23, respectively.
Results: Statistical comparisons of pharmacokinetic exposure parameters after co-administration of zavegepant and EE-LNG versus EE-LNG alone showed small, but statistically insignificant, changes in either EE or LNG exposure. EE comparison ratios (90% confidence intervals [CIs]) were 109.9% (105.3%, 114.8%) for AUC0-inf and 110.2% (104.6%, 116.1%) for Cmax. LNG comparison ratios (90% CIs) were 107.0% (100.2%, 114.3%) for AUC0-inf and 108.8% (99.9%, 118.4%) for Cmax. Frequently reported treatment-emergent adverse events included dysgeusia (n = 25, 96%), throat irritation (n = 11, 42%), headache (n = 10, 39%), nasal discomfort (n = 7, 27%), pharyngeal paresthesia (n = 5, 19%), and nausea (n = 4, 15%).
Conclusion: Co-administration of zavegepant nasal spray with a single dose of an oral contraceptive resulted in no clinically meaningful changes (<12% increase) in EE-LNG exposure.
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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