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Article(id=1212692497072050419, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1212692495675343162, articleNumber=1001-2494(2024)18-1757-07, orderNo=null, doi=10.11669/cpj.2024.18.012, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1697126400000, receivedDateStr=2023-10-13, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1767058022038, onlineDateStr=2025-12-30, pubDate=1726934400000, pubDateStr=2024-09-22, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1767058022038, onlineIssueDateStr=2025-12-30, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1767058022038, creator=13701087609, updateTime=1767058022038, updator=13701087609, issue=Issue{id=1212692495675343162, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='18', pageStart='1665', pageEnd='1778', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1767058021692, creator=13701087609, updateTime=1767058962460, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1212696441533940214, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1212692495675343162, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1212696441533940215, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1212692495675343162, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1757, endPage=1763, ext={EN=ArticleExt(id=1212692497466314997, articleId=1212692497072050419, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Safety of Small Molecule Anti-SARS-CoV-2 Drugs During Pregnancy and Lactation, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE Pregnant women are at a high risk of severe/critical SARS-CoV-2 infection, which can cause serious harm to both mothers and fetuses. Therefore, safe and effective medications are urgently needed. The current circulating strain Omicron variant JN.1 has been observed to elicit immune escape, leading to a decline in the efficacy of vaccines and neutralizing antibody drugs. As a result, the importance of small molecule antiviral drugs has become increasingly apparent, but their safety in pregnant and lactating women are not clear. METHODS Through searching domestic and international literature and databases, this paper reviews the safety data and experience of the approved small molecule anti-SARS-CoV-2 drugs (including remdesivir, molnupiravir, azvudine, renmindevir, nirmatrelvir/ritonavir, simnotrelvir/ritonavir, and leritrelvir) during pregnancy and lactation. The paper also presents information on genetic toxicity, animal and human reproductive toxicity, placental transport, and milk secretion. RESULTS Among them, the research data on remdesivir and nirmatrelvir/ritonavir are relatively sufficient. Animal studies have not found obvious reproductive toxicity, and the use of these drugs during human pregnancy has not shown serious adverse effects on mothers and fetuses. However, remdesivir is not yet listed in our country. CONCLUSION Nirmatrelvir/ritonavir may be an option for anti-SARS-CoV-2 treatment during pregnancy, and breast-feeding should be done after the drug is cleared.

, correspAuthors=Mengru BAI, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Qian SHEN, Jinqi ZHENG, Shuixian ZHANG, Mengru BAI), CN=ArticleExt(id=1212692498271621367, articleId=1212692497072050419, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=抗新型冠状病毒小分子药物在妊娠期和哺乳期的安全性, columnId=1190352405612040510, journalTitle=中国药学杂志, columnName=论著, runingTitle=null, highlight=null, articleAbstract=

目的 孕产妇是新冠感染重型/危重型高危人群,一旦感染对母婴均造成严重危害,迫切需要安全有效的防治措施。奥密克戎系列变异株JN.1的免疫逃逸能力强,疫苗和抗体药物的疗效大幅下降,小分子抗病毒药物的优势凸显。但其在孕产妇中的安全性尚不明确。方法 通过检索国内外文献及数据库,对已上市的7种抗新冠病毒小分子药物在妊娠期和哺乳期使用的安全性数据和经验,分别从遗传毒性、动物与人类生殖毒性、胎盘转运、乳汁分泌等方面进行阐述。结果 未发现明显生殖毒性及母婴不良后果,但瑞德西韦我国尚未上市。结论 权衡利弊后妊娠期可慎重使用奈玛特韦/利托那韦,待药物清除后再哺乳。

, correspAuthors=白梦如, authorNote=null, correspAuthorsNote=
* 白梦如,女,博士,主管药师 研究方向:孕哺乳期药物体内分析研究 Tel: (0571)56007824
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申潜,男,硕士,主管药师 研究方向:药物质量与安全性研究

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申潜,男,硕士,主管药师 研究方向:药物质量与安全性研究

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申潜,男,硕士,主管药师 研究方向:药物质量与安全性研究

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DOI: 10.1001/jamanetworkopen.2022.44141., articleTitle=Analysis of clinical outcomes of pregnant patients treated with nirmatrelvir and ritonavir for acute SARS-CoV-2 infection, refAbstract=null), Reference(id=1212790511589572767, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212692497072050419, doi=null, pmid=null, pmcid=null, year=2023, volume=141, issue=5, pageStart=957, pageEnd=960, url=null, language=null, rfNumber=[40], rfOrder=39, authorNames=LIN C Y, CASSIDY A G, LI L, journalName=Obstet Gynecol, refType=null, unstructuredReference=LIN C Y, CASSIDY A G, LI L, et al. Nirmatrelvir-Ritonavir (Paxlovid) for mild Coronavirus Disease 2019 (COVID-19) in pregnancy and lactation[J]. Obstet Gynecol, 2023, 141(5):957-960., articleTitle=Nirmatrelvir-Ritonavir (Paxlovid) for mild Coronavirus Disease 2019 (COVID-19) in pregnancy and lactation, refAbstract=null), Reference(id=1212790511736373410, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212692497072050419, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=https://www.clinicaltrials.gov/study/NCT05386472, language=null, rfNumber=[41], rfOrder=40, authorNames=Pfizer, journalName=ClinicalTrials. gov, refType=null, unstructuredReference=Pfizer. A Study to Learn About the Study Medicine (Nirmatrelvir Plus Ritonavir) in Pregnant Women With COVID-19[DB/OL]. ClinicalTrials. gov [2024-06-04]. https://www.clinicaltrials.gov/study/NCT05386472., articleTitle=A Study to Learn About the Study Medicine (Nirmatrelvir Plus Ritonavir) in Pregnant Women With COVID-19, refAbstract=null), Reference(id=1212790511832842404, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212692497072050419, doi=null, pmid=null, pmcid=null, year=2023, volume=20, issue=2, pageStart=40, pageEnd=53, url=null, language=null, rfNumber=[42], rfOrder=41, authorNames=Zhejiang Quality Control Center For Hospital Drug Affairs, journalName=Chin J Rational Drug Use(中国合理用药探索), refType=null, unstructuredReference=Zhejiang Quality Control Center For Hospital Drug Affairs. Clinical issues and pharmaceutical recommendations for Nirmatrelvir Tablets/Ritonavir Tablets (Co-Packaged): clinical medication recommendations for COVID-19 (Ⅰ)[J]. Chin J Rational Drug Use(中国合理用药探索), 2023, 20(2):40-53., articleTitle=Clinical issues and pharmaceutical recommendations for Nirmatrelvir Tablets/Ritonavir Tablets (Co-Packaged): clinical medication recommendations for COVID-19 (Ⅰ), refAbstract=null), Reference(id=1212790511908339878, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212692497072050419, doi=null, pmid=null, pmcid=null, year=2023, volume=47, issue=7, pageStart=484, pageEnd=488, url=null, language=null, rfNumber=[43], rfOrder=42, authorNames=LU L, WU Q, WANG F, XIANNUOXIN®, journalName=Prog Pharm Sci, refType=null, unstructuredReference=LU L, WU Q, WANG F. XIANNUOXIN®: China's first anti-SARS-CoV-2 drug targeting 3C-like protease[J]. Prog Pharm Sci (药学进展), 2023, 47(7):484-488., articleTitle=China's first anti-SARS-CoV-2 drug targeting 3C-like protease, refAbstract=null), Reference(id=1212790511979643048, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212692497072050419, doi=null, pmid=null, pmcid=null, year=2022, volume=57, issue=3, pageStart=615, pageEnd=626, url=null, language=null, rfNumber=[44], rfOrder=43, authorNames=YANG H Y, ZHENG L, YU B, journalName=Acta Pharm Sin(药学学报), refType=null, unstructuredReference=YANG H Y, ZHENG L, YU B, et al. Changes of pharmacokinetics and application of physiologically based pharmacokinetic modeling in pharmacotherapy during pregnancy[J]. 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药物 靶点 妊娠期 哺乳期 育龄女性
胎盘转运 生殖毒性 目前建议 乳汁分泌 目前建议 遗传毒性 目前建议
瑞德西韦 RdRp 是(大鼠,代谢物GS-441524;人离体胎盘) 否(大鼠、家兔、人) 权衡利弊 是(大鼠;人) ≥28 d(体质量≥3 kg)的婴儿:可以哺乳;
<28 d的新生儿:用药期间和末次用药后135 h内暂停哺乳		 阴性 不明确
莫诺拉韦 RdRp 是(大鼠,代谢物EIDD-1931) 是(大鼠、家兔) 避免使用 是(大鼠,代谢物EIDD-1931) 用药期间和末次用药后4 d内暂停哺乳 部分阳性 用药期间和末次用药后4 d内避孕
阿兹夫定 RdRp 未知 是(大鼠、家兔) 避免使用 是(大鼠) 阳性
氢溴酸氘瑞米德韦 RdRp 是(大鼠,代谢物116-N1) 是(大鼠、家兔) 避免使用 是(大鼠,代谢物116-N1) 用药期间和末次用药后7 d内暂停哺乳 阴性 用药期间和末次用药后7 d内避孕
奈玛特韦/利托那韦 3CLpro 未知 否(大鼠、人)
是(家兔,10倍血药浓度-时间曲线下面积(AUC)时,胎仔体质量降低9%)		 权衡利弊 未知 阴性
先诺特韦/利托那韦 3CLpro 是(大鼠、兔) 是(大鼠)
否(家兔)		 避免使用 是(大鼠) 阴性
来瑞特韦 3CLpro 是(大鼠) 否(大鼠) 避免使用 未知 阴性
), ArticleFig(id=1212790506602546167, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1212692497072050419, language=CN, label=表1, caption=

抗新型冠状病毒小分子药物的妊娠期与哺乳期安全性

, figureFileSmall=null, figureFileBig=null, tableContent=
药物 靶点 妊娠期 哺乳期 育龄女性
胎盘转运 生殖毒性 目前建议 乳汁分泌 目前建议 遗传毒性 目前建议
瑞德西韦 RdRp 是(大鼠,代谢物GS-441524;人离体胎盘) 否(大鼠、家兔、人) 权衡利弊 是(大鼠;人) ≥28 d(体质量≥3 kg)的婴儿:可以哺乳;
<28 d的新生儿:用药期间和末次用药后135 h内暂停哺乳		 阴性 不明确
莫诺拉韦 RdRp 是(大鼠,代谢物EIDD-1931) 是(大鼠、家兔) 避免使用 是(大鼠,代谢物EIDD-1931) 用药期间和末次用药后4 d内暂停哺乳 部分阳性 用药期间和末次用药后4 d内避孕
阿兹夫定 RdRp 未知 是(大鼠、家兔) 避免使用 是(大鼠) 阳性
氢溴酸氘瑞米德韦 RdRp 是(大鼠,代谢物116-N1) 是(大鼠、家兔) 避免使用 是(大鼠,代谢物116-N1) 用药期间和末次用药后7 d内暂停哺乳 阴性 用药期间和末次用药后7 d内避孕
奈玛特韦/利托那韦 3CLpro 未知 否(大鼠、人)
是(家兔,10倍血药浓度-时间曲线下面积(AUC)时,胎仔体质量降低9%)		 权衡利弊 未知 阴性
先诺特韦/利托那韦 3CLpro 是(大鼠、兔) 是(大鼠)
否(家兔)		 避免使用 是(大鼠) 阴性
来瑞特韦 3CLpro 是(大鼠) 否(大鼠) 避免使用 未知 阴性
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抗新型冠状病毒小分子药物在妊娠期和哺乳期的安全性
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申潜 1 , 郑金琪 1 , 张水仙 2 , 白梦如 2, *
中国药学杂志 | 论著 2024,59(18): 1757-1763
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中国药学杂志 | 论著 2024, 59(18): 1757-1763
抗新型冠状病毒小分子药物在妊娠期和哺乳期的安全性
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申潜1, 郑金琪1, 张水仙2, 白梦如2, *
作者信息
  • 1 浙江省食品药品检验研究院, 浙江省原料药安全研究中心, 杭州 310052
  • 2 杭州市第一人民医院, 杭州 310006

    • 申潜,男,硕士,主管药师 研究方向:药物质量与安全性研究

通讯作者:

* 白梦如,女,博士,主管药师 研究方向:孕哺乳期药物体内分析研究 Tel: (0571)56007824
Safety of Small Molecule Anti-SARS-CoV-2 Drugs During Pregnancy and Lactation
Qian SHEN1, Jinqi ZHENG1, Shuixian ZHANG2, Mengru BAI2, *
Affiliations
  • 1 Zhejiang Research Center for API Security, Zhejiang Institute for Food and Drug Control, Hangzhou 310052, China
  • 2 Hangzhou First People's Hospital, Hangzhou 310006, China
出版时间: 2024-09-22 doi: 10.11669/cpj.2024.18.012
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摘要
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目的 孕产妇是新冠感染重型/危重型高危人群,一旦感染对母婴均造成严重危害,迫切需要安全有效的防治措施。奥密克戎系列变异株JN.1的免疫逃逸能力强,疫苗和抗体药物的疗效大幅下降,小分子抗病毒药物的优势凸显。但其在孕产妇中的安全性尚不明确。方法 通过检索国内外文献及数据库,对已上市的7种抗新冠病毒小分子药物在妊娠期和哺乳期使用的安全性数据和经验,分别从遗传毒性、动物与人类生殖毒性、胎盘转运、乳汁分泌等方面进行阐述。结果 未发现明显生殖毒性及母婴不良后果,但瑞德西韦我国尚未上市。结论 权衡利弊后妊娠期可慎重使用奈玛特韦/利托那韦,待药物清除后再哺乳。

奈玛特韦/利托那韦  /  瑞德西韦  /  新型冠状病毒  /  妊娠期  /  哺乳期

OBJECTIVE Pregnant women are at a high risk of severe/critical SARS-CoV-2 infection, which can cause serious harm to both mothers and fetuses. Therefore, safe and effective medications are urgently needed. The current circulating strain Omicron variant JN.1 has been observed to elicit immune escape, leading to a decline in the efficacy of vaccines and neutralizing antibody drugs. As a result, the importance of small molecule antiviral drugs has become increasingly apparent, but their safety in pregnant and lactating women are not clear. METHODS Through searching domestic and international literature and databases, this paper reviews the safety data and experience of the approved small molecule anti-SARS-CoV-2 drugs (including remdesivir, molnupiravir, azvudine, renmindevir, nirmatrelvir/ritonavir, simnotrelvir/ritonavir, and leritrelvir) during pregnancy and lactation. The paper also presents information on genetic toxicity, animal and human reproductive toxicity, placental transport, and milk secretion. RESULTS Among them, the research data on remdesivir and nirmatrelvir/ritonavir are relatively sufficient. Animal studies have not found obvious reproductive toxicity, and the use of these drugs during human pregnancy has not shown serious adverse effects on mothers and fetuses. However, remdesivir is not yet listed in our country. CONCLUSION Nirmatrelvir/ritonavir may be an option for anti-SARS-CoV-2 treatment during pregnancy, and breast-feeding should be done after the drug is cleared.

nirmatrelvir/ritonavir  /  remdesivir  /  SARS-CoV-2  /  pregnancy  /  lactation
申潜, 郑金琪, 张水仙, 白梦如. 抗新型冠状病毒小分子药物在妊娠期和哺乳期的安全性. 中国药学杂志, 2024 , 59 (18) : 1757 -1763 . DOI: 10.11669/cpj.2024.18.012
Qian SHEN, Jinqi ZHENG, Shuixian ZHANG, Mengru BAI. Safety of Small Molecule Anti-SARS-CoV-2 Drugs During Pregnancy and Lactation[J]. Chinese Pharmaceutical Journal, 2024 , 59 (18) : 1757 -1763 . DOI: 10.11669/cpj.2024.18.012
正文
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新型冠状病毒感染(COVID-19)是一种由新型冠状病毒(SARS-CoV-2)引起的急性呼吸道传染病,以发热、干咳和乏力为主要临床表现,重症患者出现呼吸困难、低氧血症等症状,严重者可快速进展为急性呼吸窘迫综合征、脓毒症休克、多器官衰竭甚至死亡。人类对SARS-CoV-2普遍易感,其传染性极强[1]。
妊娠期女性是一个特殊的群体,妊娠期间机体处于部分免疫抑制状态,且心肺负荷生理性加重,加之孕妇新冠疫苗接种率普遍偏低[2],孕妇感染SARS-CoV-2并进展为重症的风险较高[3]。而晚期妊娠和围产期女性更是属于COVID-19重型/危重型高危人群[1,4],一旦感染对孕妇自身健康和胎儿发育均造成严重危害。真实世界研究发现[5-10],感染SARS-CoV-2的孕妇发生严重并发症的风险更高,需要重症监护(ICU)、有创通气和体外膜肺氧合甚至孕产妇死亡的比例增加,且发生流产、早产、胎儿窘迫、胎儿生长受限、死胎等概率也显著增加,造成严重不良母婴结局,因此迫切需要安全有效的预防和治疗策略。目前奥密克戎(Omicron)是全球主要流行株,尽管初步数据表明妊娠期间感染奥密克戎变异株发生母胎严重并发症的风险低于之前的变异株,但由于病毒传播速度快,受害人群广,其临床危害仍值得关注[11]。
与COVID-19疫情初期无药可用的窘境不同,目前多种单克隆抗体和小分子抗病毒药物被成功研发上市。但由于奥密克戎免疫逃逸能力强,现有疫苗和抗体药物的疗效出现了大幅下降的现象[1,12],而抗SARS-CoV-2小分子药物具有广谱作用、不易耐药、使用简单方便、可及性好、依从性高等优势,目前对奥密克戎仍具有较好的活性,已广泛应用于临床。该类药物主要集中于两个靶点:RNA依赖性RNA聚合酶(RNA-dependent RNA polymerase,RdRp)和3CL蛋白酶(3C-like protease,3CLpro)。
由于伦理的限制,妊娠期和哺乳期女性在临床试验中通常被排除在外,极大地限制了抗新冠病毒小分子药物在该类人群中的应用。而妊娠期和哺乳期用药安全性需了解以下几个重要问题:药物是否可以透过胎盘屏障、对胎儿是否有致畸性或发育毒性、是否可分泌入乳汁及对婴儿是否有害等[13]。笔者以“新型冠状病毒、瑞德西韦、莫诺拉韦、阿兹夫定、氢溴酸氘瑞米德韦、奈玛特韦/利托那韦、先诺特韦/利托那韦、来瑞特韦、妊娠、胎盘、孕期、哺乳”等为关键词,通过计算机检索PubMed、中国知网、万方、Clinicaltrial等数据库,共收集到135篇文献,将重复者及与本文目的无关者剔除后,共纳入47篇。笔者就7种药物在妊娠期和哺乳期的安全性,以期对临床用药提供较全面的参考信息。
1 RdRp抑制剂
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RdRp是一类以病毒RNA为模板、4种核苷三磷酸为底物合成RNA的RNA合成酶,RNA病毒的转录及基因组复制过程均需要由RdRp来主导完成[14]。RdRp 抑制剂先后已有瑞德西韦、莫诺拉韦、阿兹夫定、氢溴酸氘瑞米德韦等获批上市。由于SARS-CoV-2的RdRp结构高度保守,上述药物对包括奥密克戎在内的各种变异株均有较强的抑制活性。
1.1 瑞德西韦
瑞德西韦(remdesivir,GS-5734)是美国吉利德科学公司开发的一款核苷类似物前药,粉针剂,静脉滴注给药。该药于2020年10月被美国食品药品监督管理局(Food and Drug Administration,FDA)批准用于成人及儿科(12岁及以上且体质量至少40 kg)的COVID-19患者,2022年4月将适用人群扩大到出生≥28 d及以上儿童(体质量≥3 kg),但至今在中国未获批[15]。瑞德西韦进入体内后迅速转化为代谢物GS-441524,再发生连续的磷酸化,最终形成三磷酸酯活性形式发挥抗病毒作用[16]。
在细菌诱变、人外周血淋巴细胞染色体畸变和大鼠体内微核试验中,瑞德西韦未显示出遗传毒性。大鼠自妊娠第6~17天,家兔自妊娠第7~20天(均为器官发生期)静脉注射瑞德西韦[以GS-441524的系统暴露量(AUC)计,约为人推荐剂量的4倍],胚胎-胎仔发育未见异常。瑞德西韦不会通过大鼠胎盘进入胎仔体内,但其代谢物GS-441524很容易通过胎盘,母胎转移率约为(0.51±0.18)[17]。
1项单中心回顾性队列研究显示,新冠感染症状出现7 d内使用瑞德西韦的孕妇相比7 d后使用组,其ICU住院率、住院时间等临床结局明显改善[18]。多位学者研究了瑞德西韦在妊娠期应用的临床反应,认为妊娠中晚期使用瑞德西韦的耐受性良好,严重不良事件的风险较低[19-20]。还有一项临床试验比较了瑞德西韦在美国妊娠(17例)与非妊娠(23例)女性中治疗COVID-19的药动学和安全性,初步结果显示瑞德西韦在两组人群的AUC(1 246.57 vs. 1 302.75 ng·h·mL-1)、半衰期(1.01 vs. 1.09 h)、几何平均谷浓度(51.6 vs. 57.1 ng·mL-1)无明显差异[21],提示妊娠女性使用瑞德西韦可能无须调整剂量。但上述研究仍存在诸多局限,如病例量较少,无孕早期暴露研究,未进行子代随访等。有研究者利用人离体胎盘小叶灌注模型考察瑞德西韦的跨胎盘转运情况[22],结果发现,灌注3 h后瑞德西韦和GS-441524的胎儿/母体浓度比分别为0.22和0.16,胎儿转移率分别为8.15%和9.9%,且存在性别差异,可见瑞德西韦及其代谢物可经人胎盘转运。因此,建议只有在母胎获利大于潜在风险的情况下才可使用,并密切监测其不良影响。
大鼠围产期发育毒性实验中,自妊娠第6天至哺乳期第20天,每天静脉注射瑞德西韦(以GS-441524的AUC计,约相当于人的推荐剂量),在其幼崽的血浆中检测到瑞德西韦及其代谢物,推测瑞德西韦和/或其代谢物能分泌至大鼠乳汁中,幼崽的系统暴露量约为母鼠的1%,而发育未见异常。
日本1例个案报道[23]称人乳汁中瑞德西韦与哺乳母亲血清的浓度比为0.089,婴儿相对剂量为0.007,均较低,但该研究未检测瑞德西韦的代谢物。GS-441524的相对分子质量小(仅291.27),血浆蛋白结合率低(约2%),推测较易分泌至人乳汁中。结合该药获批人群,笔者认为瑞德西韦治疗期间对于>28 d(体质量>3 kg)的婴儿母乳喂养较为安全;对于<28 d的新生儿,建议暂停哺乳,而GS-441524的半衰期约为27 h,最好经过5个半衰期后再恢复哺乳。
1.2 莫诺拉韦
莫诺拉韦(mmlnupiravir, MK-4482, EIDD-2801)是默克公司研发的全球首个上市的小分子口服抗新冠病毒药物。该药于2021年11月在英国获批,同年12月美国FDA紧急授权批准其用于成人COVID-19患者,2022年12月被我国国家药品监督管理局(NMPA)附条件批准,曾译名有莫努匹韦、莫那匹韦等[24]。莫诺拉韦也是一种前药,口服后立即水解代谢为N4-羟基胞苷(EIDD-1931)并被吸收入血,最终形成三磷酸酯活性形式发挥抗病毒作用[25]。
莫诺拉韦和代谢物EIDD-1931在Ames试验中呈阳性,表明具有一定的遗传毒性。妊娠大鼠在器官形成期口服莫诺拉韦(以EIDD-1931的AUC计,约为人推荐剂量的3倍),出现胎仔体质量下降和骨化延迟;给予人推荐剂量的8倍时,出现母鼠摄食量减少和体质量下降,也观察到胚胎着床后丢失,眼、肾脏和中轴骨骼畸形,肋骨变异;妊娠家兔给予人推荐剂量的18倍时,母兔摄食量和体质量增量减少,排便量异常,胎仔体质量降低。1项研究报道妊娠16 d的大鼠经静脉注射莫诺拉韦后,胎鼠、胎盘和羊水中立即检测到莫诺拉韦及代谢物EIDD-1931,其中莫诺拉韦浓度快速降低,而EIDD-1931则维持较高浓度,EIDD-1931的母胎转移率为(0.29±0.11)[26]。
目前尚无妊娠女性使用莫诺拉韦的相关临床研究。EIDD-1931相对分子质量较小(259.22),水溶性较高,且不与血浆蛋白结合,推测可能部分经人胎盘转运,而莫诺拉韦的动物生殖毒性较为明显,因此妊娠期间不建议服用莫诺拉韦,育龄女性在用药期间及末次用药后4 d内应避孕[27]。
大鼠围产期发育毒性实验中,口服莫诺拉韦(以EIDD-1931的AUC计,约等于人推荐剂量)后,其幼崽血浆中检测到EIDD-1931,表明莫诺拉韦或EIDD-1931可进入大鼠乳汁,但对母鼠和幼崽未见不良影响。
目前尚无关于人乳中是否存在莫诺拉韦或其代谢物的报道。莫诺拉韦口服后人体内基本无原型,而代谢物EIDD-1931的血药浓度较高,其相对分子质量较小且不与血浆蛋白结合,推测其可能分泌入人乳汁。因此,建议莫诺拉韦服药期间及治疗结束后4 d内暂停哺乳[27]。
1.3 阿兹夫定
阿兹夫定(azvudine,FNC)是我国首个自主研发的小分子抗新冠病毒药物,由河南真实生物科技有限公司、郑州大学、河南师范大学等单位共同开发[28]。该药于2021年7月被我国NMPA附条件批准用于治疗高病毒载量的成年人类免疫缺陷病毒(HIV-1)感染患者,2022年7月被NMPA附条件批准用于成人普通型COVID-19[29]。阿兹夫定进入宿主细胞后,经激酶催化转化为活性化合物核苷三磷酸,从而抑制病毒复制[30-31]。
阿兹夫定的3项遗传毒性试验即Ames实验、体外中国仓鼠肺细胞染色体畸变实验和小鼠体内骨髓细胞微核实验结果均为阳性。妊娠大鼠口服阿兹夫定1.5 mg·kg-1·d-1时(以mg·m-2计,约为人推荐剂量的4.8倍;以AUC计,约为人推荐剂量的729倍),可引起吸收胎,着床后丢失,胎仔体质量、身长降低,骨骼发育迟缓。妊娠家兔剂量为3.0 mg·kg-1·d-1时(以AUC计,约为人推荐剂量的405倍),出现胚胎及胎仔发育毒性,如早期吸收胎,着床后丢失,胎仔体质量、身长降低,骨骼畸形率升高;同时出现母体毒性,如妊娠后期体质量增加、摄食量降低,子宫、卵巢重量降低。
由于阿兹夫定的遗传毒性和动物生殖毒性,目前尚未开展阿兹夫定临床妊娠期安全性的相关研究。由于其相对分子质量小(286.22)且血浆蛋白结合率低,而水溶性较高,推测可能部分经人胎盘转运,不建议妊娠期患者使用阿兹夫定,育龄女性在用药期间及末次用药后4 d内应避孕[31]。
大鼠围产期发育毒性实验中,剂量为0.5~5 mg·kg-1·d-1时,在乳汁中检测到阿兹夫定,表明阿兹夫定可经大鼠乳汁排出,并且致母体毒性包括体质量、摄食量、子宫重量降低,甚至母体死亡;同时子代体质量、哺育成活率降低,阴道张开及阴茎龟头包皮裂开时间延长,翻正反射及悬崖回避阳性率和学习能力降低。
阿兹夫定能否进入人乳汁尚无报道,但其相对分子质量小,与人血浆蛋白结合程度较低,推测可能分泌进入人乳汁,建议服药期间及治疗结束后4 d暂停哺乳[32]。
1.4 氢溴酸氘瑞米德韦
氢溴酸氘瑞米德韦(renmindevir,VV116)是由中国科学院上海药物研究所、武汉病毒研究所、苏州旺山旺水生物医药有限公司、上海君实生物医药科技股份有限公司等共同研发的我国1类创新药。该药于2021年底在乌兹别克斯坦获批,2023年1月经我国NMPA附条件批准用于成人COVID-19患者[33]。VV116是从瑞德西韦的母体核苷结构基础上优化而来,氘替换氢,使化学键更稳定不容易被代谢,再键合3个异丁酸酯改良成更方便使用的口服片剂。VV116进入体内后被代谢成核苷形式116-N1,在细胞内进一步形成三磷酸活性形式发挥抗病毒作用[34]。
VV116的3项遗传毒性试验均为阴性。妊娠大鼠每天口服氢溴酸氘瑞米德韦,≥200 mg·kg-1·d-1(以AUC计,相当于临床推荐剂量的6倍)剂量下,胎仔出现骨骼变异;在出现母体毒性的高剂量500 mg·kg-1·d-1(以AUC计,相当于人推荐剂量的11.3倍)时,还可见胎仔体质量和顶臀长轻微降低。妊娠家兔剂量为≥150 mg·kg-1·d-1(以AUC计,相当于人推荐剂量的5.6倍)时,可见母体毒性、活胎数减少、着床后丢失率增加,未见致畸性。
目前尚无关于VV116影响人体生育力及胎儿发育情况的报道,也无妊娠患者使用该药的数据。由于VV116的活性代谢物116-N1与瑞德西韦的代谢物GS-441524仅相差1个氘原子,且116-N1的人血浆蛋白结合率较低(24.9%),推测116-N1可经人胎盘转运。因此,妊娠期不建议使用VV116,育龄女性在用药期间及末次用药后7 d内应避孕。
在大鼠围产期发育毒性实验中,母鼠每天口服氢溴酸氘瑞米德韦,胎仔和仔鼠血浆中均检测到116-N1,提示其可透过大鼠胎盘和经乳汁分泌,但在高剂量200 mg·kg-1·d-1(以AUC计,相当于人推荐剂量的6倍)时未见对母鼠生殖和子代发育的影响。
VV116及其代谢物是否经人乳汁分泌尚不明确。药物口服后人体内基本无VV116原型,而代谢物116-N1的血药浓度较高,推测可分泌至人乳汁中。哺乳期患者在治疗期间和治疗结束后7 d内建议暂停母乳喂养。
2 3CLpro抑制剂
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3CLpro负责水解病毒多聚蛋白C端的大部分位点,在介导SARS-CoV-2复制和转录中起到关键作用,抑制3CLpro活性可阻止病毒的复制,且其序列具有高度保守性,不容易发生突变。3CLpro抑制剂对所有新冠病毒变异株均有效,是进行抗冠状病毒药物设计的关键靶标[35]。目前我国已上市的3CLpro抑制剂有奈玛特韦/利托那韦、先诺特韦/利托那韦和来瑞特韦。
2.1 奈玛特韦/利托那韦
奈玛特韦/利托那韦是美国辉瑞公司研发的全球首个上市的3CLpro抑制剂。2021年12月美国FDA紧急授权批准其用于治疗成人和儿童(12岁以上,体质量至少40 kg)的COVID-19患者,2022年1月加拿大卫生部批准其紧急使用,2022年2月我国NMPA附条件批准其用于成人COVID-19患者。其中,奈玛特韦(nirmatrelvir,PF-07321332)可以直接与SARS-CoV-2的3CLpro活性位点结合,发挥抗新冠病毒作用;而利托那韦是已在临床使用多年的HIV-1蛋白酶抑制剂,其本身对于新冠病毒无作用,主要是通过抑制肝药酶CYP3A4介导的奈玛特韦代谢,从而增加奈玛特韦血浆浓度增强其药效[36-37]。正是由于此,利托那韦也影响其他经CYP3A4代谢的药物的血药浓度,临床应用时需特别注意药物的相互作用。利托那韦已经常规用于HIV感染孕妇,其妊娠期安全性已经过临床验证,只需重点分析奈玛特韦的妊娠期安全性。
奈玛特韦的3项遗传毒性实验均呈阴性。妊娠大鼠在器官形成期口服奈玛特韦1 000 mg·kg-1·d-1(以AUC计,相当于人推荐剂量的8倍)时,未见对胚胎-胎仔发育的明显影响。妊娠家兔在剂量1 000 mg·kg-1·d-1(以AUC计,相当于人推荐剂量的10倍)时,可见胎仔体质量降低9%,未见其他明显发育毒性。
1项临床研究显示7名接受奈玛特韦片/利托那韦片治疗的妊娠患者(孕早期1例,孕中期2例,孕晚期4例),有1名患者出现味觉障碍,其余患者未出现不良反应,截至文章发表时已有3例分娩,亦未观察到对胎儿或新生儿的不良影响[38]。另1项多中心临床研究显示,47名新冠阳性的妊娠女性接受奈玛特韦片/利托那韦片治疗(孕早期4例,孕中期16例,孕晚期27例),其中2例因为出现不良反应而中断治疗,其余孕妇耐受良好,截至文章发表时有25例已分娩,除剖宫产率较高(约48%)之外,未出现其他严重的母儿不良后果[39]。还有1项临床研究,纳入12名妊娠期女性接受奈玛特韦片/利托那韦片治疗,有11例出现味觉障碍,2例腹泻,1例轻度腹痛,不良反应报告率较高,截至文章发表时有11例已分娩,其中有1例是双胎早产,另外10例都健康足月无并发症[40]。上述研究均有其局限性,如病例量较少、无长期随访、胎儿出生后的发育情况不明等。另外辉瑞公司正在开展一项Ⅰ期开放标签研究,旨在评估轻至中度COVID-19孕中晚期女性口服奈玛特韦/利托那韦的药动学、安全性和耐受性,目前还处于患者招募阶段,尚未公布研究数据[41]。奈玛特韦相对分子质量499.54,脂溶性较高,人血浆蛋白结合率为69%,推测可少量通过胎盘转运。因此,建议只有母亲的潜在获益大于对胎儿的潜在风险时,才能在妊娠期间使用,育龄女性在用药期间及末次用药后7 d内应避孕[42]。
奈玛特韦尚未完成大鼠围产期毒性试验,尚不清楚其是否会分泌至动物乳汁中,对授乳幼崽的影响亦不明确。
奈玛特韦是否分泌入人乳汁亦无报道。仅有1项研究报道了2名哺乳期女性接受奈玛特韦片/利托那韦片治疗,有1例出现轻微味觉改变,母亲和乳儿无其他严重不良反应[40]。由于奈玛特韦在人体的血药浓度较高,推测可进入乳汁,无法排除对新生儿/婴儿的风险,因此治疗期间及末次用药后7 d内建议暂停哺乳。
2.2 先诺特韦/利托那韦
先诺特韦/利托那韦是由先声药业、中国科学院上海药物研究所、武汉病毒研究所等共同研发的首个国产3CLpro靶点抗SARS-CoV-2创新药,2023年1月经我国NMPA附条件批准用于成人COVID-19患者[43]。先诺特韦(simnotrelvir,SIM0417)通过抑制3CLpro的活性阻止病毒复制,发挥抗新冠病毒作用;利托那韦抑制肝药酶CYP3A4活性,从而升高先诺特韦血浆浓度,因此临床应用时也需特别注意药物相互作用。
先诺特韦的3项遗传毒性试验均呈阴性。妊娠大鼠口服先诺特韦,在300和1 000 mg·kg-1·d-1,均可见胎仔胸椎椎体哑铃状异常率升高,均可见胎仔胸椎椎体哑铃状异常率升高。妊娠家兔在500 mg·kg-1·d-1(以AUC计,相当于人推荐剂量的6倍)时,未见明显母体和胚胎-胎仔发育毒性。而动物实验表明先诺特韦可透过胎盘屏障。
目前尚无妊娠女性使用先诺特韦的数据,先诺特韦相对分子质量549.63,人血浆蛋白结合率为72.5%,推测可少量通过人胎盘转运,无法排除对胎儿的风险,因此不建议妊娠期使用,育龄女性在用药期间及末次用药后7 d内应避孕。
在大鼠围产期毒性实验中,1 000 mg·kg-1·d-1剂量下,未见对妊娠/哺乳母体和子代生长发育的影响,但先诺特韦可通过大鼠乳汁分泌。
目前尚无哺乳期女性使用本药的数据,尚不清楚先诺特韦是否会分泌至人乳汁中,由于先诺特韦在人体的血药浓度高,推测可能进入人乳汁。因此治疗期间及末次用药后7 d内建议暂停哺乳。
2.3 来瑞特韦
来瑞特韦是广东众生睿创生物科技有限公司研发的1类创新药,2023年3月经我国NMPA附条件批准用于成人COVID-19患者。来瑞特韦(leritrelvir,RAY1216)不需要联用利托那韦,是国内首款单药3CLpro抑制剂。
来瑞特韦的3项遗传毒性试验均为阴性。在大鼠生育力和早期胚胎发育研究中,雄性大鼠自交配前4周至交配成功、雌性大鼠自交配前2周至妊娠第6天,每天2次口服来瑞特韦,在最高至900 mg·kg-1·d-1(以AUC计,分别相当于人推荐剂量的2.38和4.79倍)剂量时,未见其对生育力、生殖能力和早期胚胎发育的影响。在大鼠胚胎-胎仔发育毒性实验中,900 mg·kg-1·d-1剂量时,未见胚胎-胎仔发育毒性和致畸性,但来瑞特韦可以透过胎盘屏障进入胎仔。
目前尚无妊娠期和哺乳期女性使用来瑞特韦的数据,亦不清楚来瑞特韦或其任何代谢物是否会通过人胎盘转运或分泌至人乳汁中。由于来瑞特韦在人体的血药浓度高,且脂溶性高,相对分子质量639.72,血浆蛋白结合率约74.5%~79.7%,推测可部分通过人胎盘转运及分泌至乳汁,因此暂不建议妊娠患者使用,育龄女性和哺乳期女性在治疗期间及末次用药后7 d内应避孕和暂停哺乳。
3 总结
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笔者总结了已获批的抗SARS-CoV-2小分子药物在妊娠期和哺乳期安全性的国内外信息以及用药建议,见表1。由于大部分抗新冠病毒药物均可分泌入动物或人乳汁,而其对母乳喂养的婴儿的影响尚不明确,因此一般不建议使用抗病毒药物治疗的母亲母乳喂养,等药物从体内清除后再恢复哺乳。由于缺乏孕早期暴露于上述抗病毒药物的临床研究,育龄女性在用药期间也最好避免怀孕。
尽管目前尚无任何一种抗新冠病毒药物被批准用于妊娠期,但基于现有资料,瑞德西韦和奈玛特韦/利托那韦的研究数据相对充分,妊娠期使用风险相对较低,但瑞德西韦在我国未上市,因此,对于妊娠合并新冠感染的患者,临床可在权衡利弊后慎重使用奈玛特韦/利托那韦,并做好充分的知情告知。此外,女性在妊娠期会发生多重生理变化,如胃动力减退、胃液pH值升高、血容量增加、药物血浆蛋白结合降低、肾血流量和肾小球滤过率增加等[44-45],且文献[46-47]表明妊娠期肝药酶CYP3A的活性显著增加。因此,妊娠是否会改变抗病毒药物的药动学从而影响疗效,以及上述药物对胎儿的远期安全性如何,还需更多的高质量的多学科、多中心的研究,以提高孕产妇这类特殊人群用药的安全性及有效性。
基金
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  • 国家自然科学基金项目资助(82003838)
  • 浙江省自然科学基金项目资助(LY22H310006)
  • 浙江省卫生健康科技计划项目资助(2021RC021)
  • 浙江省药品监督管理局科技计划项目资助(2022001)
文献
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参考文献 引证文献
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2024年第59卷第18期
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doi: 10.11669/cpj.2024.18.012
  • 接收时间：2023-10-13
  • 首发时间：2025-12-30
  • 出版时间：2024-09-22
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  • 收稿日期：2023-10-13
基金
国家自然科学基金项目资助(82003838)
浙江省自然科学基金项目资助(LY22H310006)
浙江省卫生健康科技计划项目资助(2021RC021)
浙江省药品监督管理局科技计划项目资助(2022001)
作者信息
    1 浙江省食品药品检验研究院, 浙江省原料药安全研究中心, 杭州 310052
    2 杭州市第一人民医院, 杭州 310006

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* 白梦如,女,博士,主管药师 研究方向:孕哺乳期药物体内分析研究 Tel: (0571)56007824
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https://castjournals.cast.org.cn/joweb/zgyxzz/CN/10.11669/cpj.2024.18.012
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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