患有COVID-19的实体器官移植患者应用免疫抑制剂的策略及浓度监测推荐: 一篇多中心回顾性研究

doi:10.5246/jcps.2025.12.083

中国药学(英文版) ›› 2025, Vol. 34 ›› Issue (12): 1101-1113.DOI: 10.5246/jcps.2025.12.083

• 【研究论文】 • 上一篇

患有COVID-19的实体器官移植患者应用免疫抑制剂的策略及浓度监测推荐: 一篇多中心回顾性研究

杨辉¹^,⁸^,^#, 张颖⁷^,^#, 马葵芬²^,⁸^,^#, 刘相端⁴^,⁸^,^#, 陈娇娇⁵^,^#, 王颖⁴, 朱莹¹, 钱卿⁶^,⁸^,^*(), 侯文婧³^,⁸^,^*(), 安卓玲¹^,^*()

^1. 首都医科大学附属北京朝阳医院药事部, 北京 100020
^2. 浙江大学附属第一医院药事部, 浙江杭州 311500
^3. 首都医科大学附属北京友谊医院药事部, 北京 100050
^4. 河南中医药大学第五临床医学院(郑州人民医院) 药事部, 河南郑州 450000
^5. 烟台市毓璜顶医院药事部, 山东烟台 264001
^6. 常州第一人民医院药事部, 江苏常州 213003
^7. 陕西省人民医院药事部, 陕西西安 710068
^8. 全国移植药师联盟, 浙江杭州 311500

收稿日期:2025-08-07 修回日期:2025-08-14 接受日期:2025-09-27 出版日期:2025-12-31 发布日期:2025-12-31
通讯作者: 钱卿, 侯文婧, 安卓玲

Optimizing immunosuppressant regimens and therapeutic drug monitoring in solid organ transplant recipients with COVID-19: A multicenter retrospective study

Hui Yang¹^,⁸^,^#, Ying Zhang⁷^,^#, Kuifen Ma²^,⁸^,^#, Xiangduan Liu⁴^,⁸^,^#, Jiaojiao Chen⁵^,^#, Ying Wang⁴, Ying Zhu¹, Qing Qian⁶^,⁸^,^*(), Wenjing Hou³^,⁸^,^*(), Zhuoling An¹^,^*()

¹ Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
² Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 311500, Zhejiang, China
³ Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
⁴ Department of Pharmacy, Fifth Clinical College of Henan University of Traditional Chinese Medicine (Zhengzhou People’s Hospital), Zhengzhou 450000, Henan, China
⁵ Yantai Yuhuangding Hospital, Yantai 264001, Shandong, China
⁶ The First People’s Hospital of Changzhou, Changzhou 213003, Jiangsu, China
⁷ Department of Pharmacy, Shaanxi Provincial People’s Hospital, Xi’an 710068, Shaanxi, China
⁸ National Alliance of Transplant Pharmacists, Hangzhou 311500, Zhejiang, China

Received:2025-08-07 Revised:2025-08-14 Accepted:2025-09-27 Online:2025-12-31 Published:2025-12-31
Contact: Qing Qian, Wenjing Hou, Zhuoling An
About author:
^# They contributed equally to this manuscript.

摘要/Abstract

摘要：

奈玛特韦-利托那韦在感染新型冠状病毒的实体器官移植患者中具有良好的疗效, 而免疫抑制剂与奈玛特韦-利托那韦存在相互作用。本研究旨在为临床应用奈玛特韦-利托那韦时免疫抑制药物的调整策略提供临床建议。我们纳入了2022年12月至2023年6月期间在五家医院接受长期免疫抑制治疗以及短期奈玛特韦-利托那韦治疗的实体器官移植受者。连续数据以四分位数范围值的中位数表示, 而分类数据则表示为具有相应百分比的计数, 所有分析均采用Python 3.12完成, 共纳入103例受者。其中, 86例使用他克莫司的患者中, 停药后24小时内开始奈玛特-利托那韦时浓度最为稳定。联合用药导致显著浓度升高, 62.5%的患者浓度增加超过50%。停药超过24小时的患者中, 26.67%的患者浓度下降超过50%。在停药后3−4天内以初始剂量的30%−60%逐渐恢复用药, 可达到稳定的他克莫司浓度。建议所有策略均需定期进行血药浓度监测。11例环孢素患者中, 1例将剂量减少至低于20%, 浓度增加超过50%；其余选择停药, 其中超过50%患者浓度下降。在第2−5天恢复用药(减少或维持原剂量)显示出稳定的浓度。9例西罗莫司患者未出现极端浓度波动。建议在奈玛特韦-利托那韦治疗前24小时停用他克莫司, 并在治疗后3−4天内以初始剂量的30%−60%恢复用药, 同时进行定期血药浓度监测。对于环孢素和西罗莫司, 在药物治疗前及时停用, 并在奈玛特韦-利托那韦停药后根据血药浓度恢复免疫抑制治疗也是安全的。

关键词: 奈玛特韦-利托那韦, 实体器官移植患者, 新型冠状病毒肺炎, 免疫抑制剂

Abstract:

Nirmatrelvir-ritonavir, while effective against COVID-19 in solid organ transplant recipients, poses significant interactions with immunosuppressive agents. This study aimed to establish clinical recommendations for immunosuppressive drug adjustment strategies during nirmatrelvir-ritonavir therapy. We enrolled solid organ transplant recipients receiving long-term immunosuppressive therapy who underwent short-term nirmatrelvir-ritonavir treatment for SARS-CoV-2 infection across five hospitals between December 2022 and June 2023. Continuous variables were reported as medians with interquartile ranges, and categorical variables as counts with percentages. All analyses were conducted using Python 3.12. A total of 103 recipients were included. Among 86 patients on tacrolimus, drug concentrations remained most stable when tacrolimus was discontinued within 24 h prior to nirmatrelvir-ritonavir initiation. Co-administration led to marked increases in tacrolimus levels, with 62.5% of patients experiencing > 50% elevations. Delaying discontinuation beyond 24 h increased the proportion of patients with > 50% declines in concentration (26.67%). Gradual reintroduction at 30%–60% of the original dose within 3–4 d post-therapy consistently stabilized tacrolimus levels, emphasizing the need for close blood concentration monitoring. In 11 cyclosporine-treated patients, one who reduced the dose to < 20% experienced a > 50% increase in concentration, while others who discontinued cyclosporine saw > 50% decreases. Resumption of cyclosporine at reduced or original doses between days 2 and 5 generally restored stable concentrations. For nine patients receiving sirolimus, no extreme fluctuations in drug levels were observed. Based on these findings, we recommend discontinuing tacrolimus 24 h before initiating nirmatrelvir-ritonavir, followed by reintroduction at 30%–60% of the baseline dose within 3–4 d, alongside routine blood level monitoring. For patients on cyclosporine or sirolimus, temporary discontinuation prior to antiviral therapy and dose adjustments guided by post-therapy drug levels appear to be safe and effective strategies.

Key words: Nirmatrelvir/Ritonavir, Solid organ transplant recipients, COVID-19, Immunosuppressive drugs

Supporting:

杨辉, 张颖, 马葵芬, 刘相端, 陈娇娇, 王颖, 朱莹, 钱卿, 侯文婧, 安卓玲. 患有COVID-19的实体器官移植患者应用免疫抑制剂的策略及浓度监测推荐: 一篇多中心回顾性研究[J]. 中国药学(英文版), 2025, 34(12): 1101-1113.

Hui Yang, Ying Zhang, Kuifen Ma, Xiangduan Liu, Jiaojiao Chen, Ying Wang, Ying Zhu, Qing Qian, Wenjing Hou, Zhuoling An. Optimizing immunosuppressant regimens and therapeutic drug monitoring in solid organ transplant recipients with COVID-19: A multicenter retrospective study[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(12): 1101-1113.

图/表 6

Table 1. Baseline characteristics of solid organ transplant recipients using nirmatrelvir/ritonavir.

Table 2. The regimen and concentration of immunosuppressants used by patients during COVID-19 infection.

Figure 1. Distribution of patients who discontinued tacrolimus prior to initiating nirmatrelvir/ritonavir, stratified by adjustment strategies. Note: Patients are grouped according to the timing of immunosuppressant discontinuation. The two vertical lines delineate the period of nirmatrelvir/ritonavir administration. Empty boxes indicate the timing of immunosuppressant reinitiation. The two horizontal lines denote the target trough concentration range.

Figure 2. Distribution of patients who resumed tacrolimus after discontinuing nirmatrelvir/ritonavir, stratified by adjustment strategies. Note: Patients are grouped based on the timing of immunosuppressant resumption. The two vertical lines indicate the period of nirmatrelvir/ritonavir administration. Empty boxes mark the timing of immunosuppressant reinitiation. The two horizontal lines denote the target trough concentration range.

Figure 3. Cyclosporine concentration curve in solid organ transplant recipients during COVID-19 infection. Note: The two vertical lines indicate the period of nirmatrelvir/ritonavir administration. Empty boxes mark the timing of immunosuppressant reinitiation. The two horizontal lines denote the target trough concentration range.

Figure 4. Sirolimus concentration curve in solid organ transplant recipients during COVID-19 infection. Note: The two vertical lines indicate the period of nirmatrelvir/ritonavir administration. Empty boxes mark the timing of immunosuppressant reinitiation. The two horizontal lines denote the target trough concentration range.

参考文献 20

[1]	Hall, V.G.; Solera, J.T.; Al-Alahmadi, G.; Marinelli, T.; Cardinal, H.; Poirier, C.; Huard, G.; Ramesh Prasad, G.V.; De Serres, S.A.; Isaac, D.; Mainra, R.; Lamarche, C.; Sapir-Pichhadze, R.; Gilmour, S.; Humar, A.; Kumar, D. Severity of COVID-19 among solid organ transplant recipients in Canada, 2020–2021: a prospective, multicentre cohort study. Can. Med. Assoc. J. 2022, 194, E1155–E1163.
[2]	Pereira, M.R.; Mohan, S.; Cohen, D.J.; Husain, S.A.; Dube, G.K.; Ratner, L.E.; Arcasoy, S.; Aversa, M.M.; Benvenuto, L.J.; Dadhania, D.M.; Kapur, S.; Dove, L.M.; Brown, R.S.; Rosenblatt, R.E.; Samstein, B.; Uriel, N.; Farr, M.A.; Satlin, M.; Small, C.B.; Walsh, T.J.; Kodiyanplakkal, R.P.; Miko, B.A.; Aaron, J.G.; Tsapepas, D.S.; Emond, J.C.; Verna, E.C. COVID-19 in solid organ transplant recipients: Initial report from the US epicenter. Am. J. Transplant. 2020, 20, 1800–1808.
[3]	Jager, K.J.; Kramer, A.; Chesnaye, N.C.; Couchoud, C.; Sánchez-Álvarez, J.E.; Garneata, L.; Collart, F.; Hemmelder, M.H.; Ambühl, P.; Kerschbaum, J.; Legeai, C.; del Pinoy Pino, M.D.; Mircescu, G.; Mazzoleni, L.; Hoekstra, T.; Winzeler, R.; Mayer, G.; Stel, V.S.; Wanner, C.; Zoccali, C.; Massy, Z.A. Results from the ERA-EDTA Registry indicate a high mortality due to COVID-19 in dialysis patients and kidney transplant recipients across Europe. Kidney Int. 2020, 98, 1540–1548.
[4]	Devresse, A.; Briol, S.; De Greef, J.; Lemaitre, F.; Boland, L.; Haufroid, V.; Scohy, A.; Kabamba, B.; Yombi, J.C.; Belkhir, L.; Darius, T.; Buemi, A.; De Potter, K.; Mantegazza, R.; Bearzatto, B.; Goffin, E.; Kanaan, N. Safety, efficacy, and relapse of nirmatrelvir-ritonavir in kidney transplant recipients infected with SARS-CoV-2. Kidney Int. Rep. 2022, 7, 2356–2363.
[5]	Hilhorst, M.; Bemelman, F.J.; Bruchfeld, A.; Fernandez-Juarez, G.M.; Floege, J.; Frangou, E.; Goumenos, D.; van Kooten, C.; Kronbichler, A.; Stevens, K.I.; Turkmen, K.; Wiersinga, W.J.; Anders, H.J. Prophylactic and early outpatient treatment of COVID-19 in patients with kidney disease: considerations from the Immunonephrology Working Group of the European Renal Association (ERA-IWG). Nephrol. Dial. Transplant. 2023, 38, 1807–1816.
[6]	Najjar-Debbiny, R.; Gronich, N.; Weber, G.; Khoury, J.; Amar, M.; Stein, N.; Goldstein, L.H.; Saliba, W. Effectiveness of paxlovid in reducing severe coronavirus disease 2019 and mortality in high-risk patients. Clin. Infect. Dis. 2023, 76, e342–e349.
[7]	Lange, N.W.; Salerno, D.M.; Jennings, D.L.; Choe, J.; Hedvat, J.; Kovac, D.; Scheffert, J.; Shertel, T.; Ratner, L.E.; Brown, R.S.; Pereira, M.R. Nirmatrelvir/ritonavir use: Managing clinically significant drug-drug interactions with transplant immunosuppressants. Am. J. Transplant. 2022, 22, 1925–1926.
[8]	Lemaitre, F.; Budde, K.; Van Gelder, T.; Bergan, S.; Lawson, R.; Noceti, O.; Venkataramanan, R.; Elens, L.; Moes, D.J.A.R.; Hesselink, D.A.; Pawinski, T.; Johnson-Davis, K.L.; De Winter, B.C.M.; Pattanaik, S.; Brunet, M.; Masuda, S.; Langman, L.J. Therapeutic drug monitoring and dosage adjustments of immunosuppressive drugs when combined with nirmatrelvir/ritonavir in patients with COVID-19. Ther. Drug Monit. 2023, 45, 191–199.
[9]	Stader, F.; Khoo, S.; Stoeckle, M.; Back, D.; Hirsch, H.H.; Battegay, M.; Marzolini, C. Stopping lopinavir/ritonavir in COVID-19 patients: duration of the drug interacting effect. J. Antimicrob. Chemother. 2020, 75, 3084–3086.
[10]	Fishbane, S.; Hirsch, J.S.; Nair, V. Special considerations for paxlovid treatment among transplant recipients with SARS-CoV-2 infection. Am. J. Kidney Dis. 2022, 79, 480–482.
[11]	Lemaitre, F.; Grégoire, M.; Monchaud, C.; Bouchet, S.; Saint-Salvi, B.; Polard, E.; Benaboud, S.; Chouchana, L.; Cracowski, J.L.; Drici, M.D.; Garraffo, R.; Guilhaumou, R.; Jonville-Bera, A.P.; Molimard, M.; Muret, P.; Peytavin, G.; Richard, V.; Solas, C. Management of drug-drug interactions with nirmatrelvir/ritonavir in patients treated for Covid-19: Guidelines from the French Society of Pharmacology and Therapeutics (SFPT). Therapies. 2022, 77, 509–521.
[12]	Wang, A.X.; Koff, A.; Hao, D.A.; Tuznik, N.M.; Huang, Y. Effect of nirmatrelvir/ritonavir on calcineurin inhibitor levels: Early experience in four SARS-CoV-2 infected kidney transplant recipients. Am. J. Transplant. 2022, 22, 2117–2119.
[13]	Salerno, D.M.; Jennings, D.L.; Lange, N.W.; Kovac, D.; Shertel, T.; Chen, J.K.; Hedvat, J.; Scheffert, J.; Brown, R.S. Jr, Pereira, M.R. Early clinical experience with nirmatrelvir/ritonavir for the treatment of COVID-19 in solid organ transplant recipients. Am. J. Transplant. 2022, 22, 2083–2088.
[14]	Berar Yanay, N.; Bogner, I.; Saker, K.; Tannous, E. Paxlovid-tacrolimus drug–drug interaction in a 23-year-old female kidney transplant patient with COVID-19. Clin. Drug Investig. 2022, 42, 693–695.
[15]	Schneider, J.; Wobser, R.; Kühn, W.; Wagner, D.; Tanriver, Y.; Walz, G. Nirmatrelvir/ritonavir treatment in SARS-CoV-2 positive kidney transplant recipients - a case series with four patients. BMC Nephrol. 2023, 24, 99.
[16]	Branch of Organ Transplantation, Chinese Medical Association; Branch of Kidney Transplantation, China International Exchange and Promotive Association for Medical and Health Care. Xue, W.J.; Tian, P.X. Chinese clinical practice guidelines for immunosuppressive therapy in kidney transplant recipients (2023 edition). Chin J. Organ Transplant. 2024, 45, 645–663.
[17]	Brunet, M.; van Gelder, T.; Åsberg, A.; Haufroid, V.; Hesselink, D.A.; Langman, L.; Lemaitre, F.; Marquet, P.; Seger, C.; Shipkova, M.; Vinks, A.; Wallemacq, P.; Wieland, E.; Woillard, J.B.; Barten, M.J.; Budde, K.; Colom, H.; Dieterlen, M.T.; Elens, L.; Johnson-Davis, K.L.; Kunicki, P.K.; MacPhee, I.; Masuda, S.; Mathew, B.S.; Millán, O.; Mizuno, T.; Moes, D.A.R.; Monchaud, C.; Noceti, O.; Pawinski, T.; Picard, N.; van Schaik, R.; Sommerer, C.; Vethe, N.T.; de Winter, B.; Christians, U.; Bergan, S. Therapeutic drug monitoring of tacrolimus-personalized therapy: second consensus report. Ther. Drug Monit. 2019, 41, 261–307.
[18]	Charlton, M.; Levitsky, J.; Aqel, B.; O’Grady, J.; Hemibach, J.; Rinella, M.; Fung, J.; Ghabril, M.; Thomason, R.; Burra, P.; Little, E.C.; Berenguer, M.; Shaked, A.; Trotter, J.; Roberts, J.; Rodriguez-Davalos, M.; Rela, M.; Pomfret, E.; Heyrend, C.; Gallegos-Orozco, J.; Saliba, F. International liver transplantation society consensus statement on immunosuppression in liver transplant recipients. Transplantation. 2018, 102, 727–743.
[19]	Committe of Liver Transplantation, Chinese College of Transplant Doctors, Chinese Medical Doctor Association; Section of Liver Transplantation, Chinese Socciety of Organ Transplantation, Chinese Medical Association. Chinese expert consensus on application of sirolimus in liver transplantation for hepatacellular carcinoma (2020 edition). Chin. J. Dig. Surg. 2020, 19, 589–597.
[20]	Giguère, P.; Deschenes, M.J.; Van Loon, M.; Hoar, S.; Fairhead, T.; Pazhekattu, R.; Knoll, G.; Karpinski, J.; Parikh, N.; McDougall, J.; McGuinty, M.; Hiremath, S. Management and outcome of COVID-19 infection using nirmatrelvir/ritonavir in kidney transplant patients. Clin. J. Am. Soc. Nephrol. 2023, 18, 913–919.

患有COVID-19的实体器官移植患者应用免疫抑制剂的策略及浓度监测推荐: 一篇多中心回顾性研究

Optimizing immunosuppressant regimens and therapeutic drug monitoring in solid organ transplant recipients with COVID-19: A multicenter retrospective study

RichHTML

可视化

摘要/Abstract

引用本文

使用本文

图/表 6

参考文献 20

相关文章 2

编辑推荐

Metrics

本文评价

[1]	刘增强, 刘文, 许凡凡. 地塞米松和甲基泼尼松龙在重症新冠肺炎患者中的临床疗效和安全性[J]. 中国药学(英文版), 2025, 34(4): 345-353.
[2]	周泽奇, 王祥斌, 张喜庆, 张园, 付彦凯, 王志贤, 粟艳, 王贺, 肖盟, 刘昌孝. 中和抗体在新型冠状病毒肺炎治疗中的重要意义: 进展与展望[J]. 中国药学(英文版), 2021, 30(2): 87-106.