Safety, Tolerability, and Pharmacokinetics of Nebulized Hydroxychloroquine: A Pilot Study in Healthy Volunteers.

IF 2 4区 医学 Q3 RESPIRATORY SYSTEM
Feras Hawari, Yasmeen Dodin, Rabab Tayyem, Samer Najjar, Hanan Kakish, Mohammed Abu Fara, Abdullah Al Zou'bi, Nasir Idkaidek
{"title":"Safety, Tolerability, and Pharmacokinetics of Nebulized Hydroxychloroquine: A Pilot Study in Healthy Volunteers.","authors":"Feras Hawari,&nbsp;Yasmeen Dodin,&nbsp;Rabab Tayyem,&nbsp;Samer Najjar,&nbsp;Hanan Kakish,&nbsp;Mohammed Abu Fara,&nbsp;Abdullah Al Zou'bi,&nbsp;Nasir Idkaidek","doi":"10.1089/jamp.2022.0062","DOIUrl":null,"url":null,"abstract":"<p><p><b><i>Background:</i></b> Early in the coronavirus disease 2019 (COVID-19) pandemic, hydroxychloroquine (HCQ) drew substantial attention as a potential COVID-19 treatment based on its antiviral and immunomodulatory effects <i>in vitro</i>. However, HCQ showed a lack of efficacy <i>in vivo</i>, and different groups of researchers attributed this failure to the insufficient drug concentration in the lung following oral administration (HCQ is only available in the market in the tablet form). Delivering HCQ by inhalation represents a more efficient route of administration to increase HCQ exposure in the lungs while minimizing systemic toxicity. In this pilot study, the safety, tolerability, and pharmacokinetics of HCQ nebulizer solution were evaluated in healthy volunteers. <b><i>Methods:</i></b> Twelve healthy participants were included in this study and were administered 2 mL of HCQ01 solution (equivalent to 25 mg of HCQ sulfate) through Aerogen<sup>®</sup> Solo, a vibrating mesh nebulizer. Local tolerability and systemic safety were assessed by forced expiratory volume in the first and second electrocardiograms, clinical laboratory results (e.g., hematology, biochemistry, and urinalysis), vital signs, and physical examinations. Thirteen blood samples were collected to determine HCQ01 systemic exposure before and until 6 hours after inhalation. <b><i>Results:</i></b> The inhalation of HCQ01 was well tolerated in all participants. The mean value of <i>C</i><sub>max</sub> for the 12 participants was 9.66 ng/mL. <i>T</i><sub>max</sub> occurred at around 4.8 minutes after inhalation and rapidly decreased thereafter. The reported systemic exposure was very low with a mean value of 5.28 (0.6-15.6) ng·h/mL. <b><i>Conclusion:</i></b> The low systemic concentrations of HCQ01 of 9.66 ng/mL reported by our study compared with 1 μg/mL previously predicted after 200 mg BID oral administration, and the safety and tolerability of HCQ01 administered as a single dose through nebulization, support the assessment of its efficacy, safety, and tolerability in further studies for the treatment of COVID-19.</p>","PeriodicalId":14940,"journal":{"name":"Journal of Aerosol Medicine and Pulmonary Drug Delivery","volume":"36 2","pages":"76-81"},"PeriodicalIF":2.0000,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Aerosol Medicine and Pulmonary Drug Delivery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1089/jamp.2022.0062","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"RESPIRATORY SYSTEM","Score":null,"Total":0}
引用次数: 2

Abstract

Background: Early in the coronavirus disease 2019 (COVID-19) pandemic, hydroxychloroquine (HCQ) drew substantial attention as a potential COVID-19 treatment based on its antiviral and immunomodulatory effects in vitro. However, HCQ showed a lack of efficacy in vivo, and different groups of researchers attributed this failure to the insufficient drug concentration in the lung following oral administration (HCQ is only available in the market in the tablet form). Delivering HCQ by inhalation represents a more efficient route of administration to increase HCQ exposure in the lungs while minimizing systemic toxicity. In this pilot study, the safety, tolerability, and pharmacokinetics of HCQ nebulizer solution were evaluated in healthy volunteers. Methods: Twelve healthy participants were included in this study and were administered 2 mL of HCQ01 solution (equivalent to 25 mg of HCQ sulfate) through Aerogen® Solo, a vibrating mesh nebulizer. Local tolerability and systemic safety were assessed by forced expiratory volume in the first and second electrocardiograms, clinical laboratory results (e.g., hematology, biochemistry, and urinalysis), vital signs, and physical examinations. Thirteen blood samples were collected to determine HCQ01 systemic exposure before and until 6 hours after inhalation. Results: The inhalation of HCQ01 was well tolerated in all participants. The mean value of Cmax for the 12 participants was 9.66 ng/mL. Tmax occurred at around 4.8 minutes after inhalation and rapidly decreased thereafter. The reported systemic exposure was very low with a mean value of 5.28 (0.6-15.6) ng·h/mL. Conclusion: The low systemic concentrations of HCQ01 of 9.66 ng/mL reported by our study compared with 1 μg/mL previously predicted after 200 mg BID oral administration, and the safety and tolerability of HCQ01 administered as a single dose through nebulization, support the assessment of its efficacy, safety, and tolerability in further studies for the treatment of COVID-19.

雾化羟氯喹的安全性、耐受性和药代动力学:健康志愿者的初步研究。
背景:在2019冠状病毒病(COVID-19)大流行早期,羟氯喹(HCQ)作为一种潜在的COVID-19治疗药物,因其体外抗病毒和免疫调节作用而受到广泛关注。然而,HCQ在体内缺乏疗效,不同的研究小组将这种失败归因于口服给药后肺部药物浓度不足(市场上只有片剂形式的HCQ)。通过吸入给予HCQ是一种更有效的给药途径,可以增加肺部的HCQ暴露,同时最大限度地减少全身毒性。在这项初步研究中,我们在健康志愿者身上评估了HCQ雾化器溶液的安全性、耐受性和药代动力学。方法:选取12名健康受试者,通过Aerogen®Solo振动网状雾化器给予2ml HCQ01溶液(相当于25mg硫酸HCQ)。通过第一次和第二次心电图的用力呼气量、临床实验室结果(如血液学、生物化学和尿液分析)、生命体征和体格检查来评估局部耐受性和全身安全性。采集13份血样,测定吸入HCQ01前后6小时的全身暴露情况。结果:所有受试者吸入HCQ01耐受良好。12名参与者的Cmax平均值为9.66 ng/mL。Tmax在吸入后4.8分钟左右出现,此后迅速下降。报告的全身暴露量非常低,平均值为5.28 (0.6-15.6)ng·h/mL。结论:本研究报告的HCQ01全身浓度为9.66 ng/mL,而先前预测的200 mg BID口服后的浓度为1 μg/mL,且HCQ01单次雾化给药的安全性和耐受性为进一步研究评估其治疗COVID-19的有效性、安全性和耐受性提供了依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
6.70
自引率
2.90%
发文量
34
审稿时长
>12 weeks
期刊介绍: Journal of Aerosol Medicine and Pulmonary Drug Delivery is the only peer-reviewed journal delivering innovative, authoritative coverage of the health effects of inhaled aerosols and delivery of drugs through the pulmonary system. The Journal is a forum for leading experts, addressing novel topics such as aerosolized chemotherapy, aerosolized vaccines, methods to determine toxicities, and delivery of aerosolized drugs in the intubated patient. Journal of Aerosol Medicine and Pulmonary Drug Delivery coverage includes: Pulmonary drug delivery Airway reactivity and asthma treatment Inhalation of particles and gases in the respiratory tract Toxic effects of inhaled agents Aerosols as tools for studying basic physiologic phenomena.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信