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The impact of extracorporeal membrane oxygenation on the exposure to isavuconazole: a plea for thorough pharmacokinetic evaluation
Critical Care ( IF 15.1 ) Pub Date : 2022-07-27 , DOI: 10.1186/s13054-022-04093-y
Beatrijs Mertens 1, 2 , Joost Wauters 3, 4 , Yves Debaveye 5, 6 , Niels Van Regenmortel 7 , Karlien Degezelle 8 , Philippe Meersseman 9 , Greet Hermans 4, 5 , Christophe Vandenbriele 10, 11 , Ruth Van Daele 1, 2 , Isabel Spriet 1, 2
Affiliation  

Extracorporeal membrane oxygenation (ECMO) is increasingly used to provide temporary (cardio)pulmonary support in patients with life-threatening respiratory and/or cardiac failure, including critically ill patients with influenza- and coronavirus disease 2019 (COVID-19)-associated acute respiratory distress syndrome. Critically ill patients often exhibit altered and variable pharmacokinetics (PK) of antimicrobials owing to pathophysiological alterations (e.g., fluid shifts, hypoalbuminemia, renal dysfunction and augmented renal clearance) and extracorporeal treatments. ECMO might significantly affect the PK of drugs due to hemodilution from circuit priming and drug sequestration in the ECMO circuit. The impact of ECMO on the PK of mold-active triazoles, such as voriconazole and isavuconazole, has become increasingly important as they are recommended as (first-line) antifungal therapies for influenza- and COVID-19-associated pulmonary aspergillosis. Based on the high lipophilicity and extensive plasma protein binding of isavuconazole, the triazole is theoretically prone to adsorption to ECMO circuits and subsequent reduction in plasma concentrations. To date, isavuconazole exposure in ECMO patients has only been documented in two case reports and a case series (n = 3) in which reduced plasma concentrations during ECMO have been suggested [1,2,3]. In this correspondence, we would like to emphasize that the suggestion of reduced isavuconazole exposure due to ECMO as such should be interpreted cautiously and that additional studies are needed to evaluate the independent impact of ECMO on the PK of isavuconazole. This is in accordance with the mold-active triazoles voriconazole and posaconazole, for which drug sequestration into the ECMO circuit has been suggested by ex vivo studies and case reports. However, an independent effect of ECMO could not be confirmed in larger retrospective [4] or prospective studies [5].

We here report isavuconazole trough concentrations (Cmin), which were measured during routine care in four critically ill patients with concomitant isavuconazole and veno-venous ECMO treatment (approval from the local Ethics Committee; S65215). For each patient, information on ECMO and isavuconazole treatment is depicted in Fig. 1. Demographic and clinical characteristics are summarized in Additional file 1.

Fig. 1
figure 1

Treatment course of cases A, B, C and D. Grey shaded area: extracorporeal membrane oxygenation support; points: isavuconazole trough concentrations (mg/L); black short lines: isavuconazole daily doses (mg); black dashed horizontal line: minimal isavuconazole trough concentration threshold of 1 mg/L, based on the European Committee on Antimicrobial Susceptibility Testing breakpoints for Aspergillus fumigatus, A. flavus and A. terreus; grey dashed vertical line: lung transplantation. Cmin: trough concentration; Tx: transplantation

Full size image

In our case series, isavuconazole exposure was highly variable and four Cmin were lower than 1 mg/L, which can be advocated as the minimum Cmin threshold, based on the European Committee on Antimicrobial Susceptibility Testing breakpoints for Aspergillus fumigatus, A. flavus and A. terreus. Multiple factors might contribute to the variability in isavuconazole Cmin, including administered doses, treatment duration and time needed to reach steady state after therapy initiation/dose adjustment. Dose-corrected Cmin are presented in Additional file 1: file 2. The Cmin in cases A and B suggest that adequate isavuconazole exposure can be achieved during ECMO support with a standard dosing regimen. In case A, a Cmin of 4.3 mg/L was reached with an increased maintenance dose of 200 mg q12h. Considering the linear PK of isavuconazole, it could be hypothesized that a standard dose of 200 mg q24h would have resulted in a Cmin > 1 mg/L. In case B, this minimal target Cmin was achieved with a standard maintenance dose. In contrast, the isavuconazole Cmin in cases C and D did not exceed the target of 1 mg/L when correcting for the standard maintenance dose of 200 mg q24h. The latter results are in line with the previous reports by Zhao et al. [3] and Miller et al. [1], in which subtherapeutic exposure following a standard dosing regimen was documented and ascribed to ECMO as such.

Unfortunately, based on the previously published reports [1,2,3] and our case series, the independent impact of ECMO on isavuconazole exposure in critically ill patients cannot be assessed. Therefore, the key question whether subtherapeutic isavuconazole exposure in ECMO patients is caused by ECMO or by critical illness itself remains unanswered. This evidence gap underlines the need for large PK evaluations in critically ill patients, including those with augmented renal clearance, hypoalbuminemia, hepatic and renal dysfunction, renal replacement therapy and ECMO. Pending additional data (e.g., ICONIC study, ClinicalTrials.gov: NCT04777058), therapeutic drug monitoring of isavuconazole is warranted in critically ill patients, both in ECMO and non-ECMO patients.

Individual participant data that underlie the results reported in this manuscript are available from the corresponding author upon reasonable request, providing the request meets the local ethical and research governance criteria after publication. Patient data will be anonymized and study documents will be redacted to protect the privacy of participants.

C min :

Trough concentration

ECMO:

Extracorporeal membrane oxygenation

PK:

Pharmacokinetic

T x :

Transplantation

  1. Miller M, Kludjian G, Mohrien K, Morita K. Decreased isavuconazole trough concentrations in the treatment of invasive aspergillosis in an adult patient receiving extracorporeal membrane oxygenation support. Am J Health Syst Pharm. 2022;79(15):1245—9.

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  3. Zhao Y, Seelhammer TG, Barreto EF, Wilson JW. Altered pharmacokinetics and dosing of liposomal amphotericin B and isavuconazole during extracorporeal membrane oxygenation. Pharmacotherapy. 2020;40(1):89–95.

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  4. Van Daele R, Bekkers B, Lindfors M, Broman LM, Schauwvlieghe A, Rijnders B, Hunfeld NGM, Juffermans NP, Taccone FS, Coimbra Sousa CA, et al. A large retrospective assessment of voriconazole exposure in patients treated with extracorporeal membrane oxygenation. Microorganisms. 2021;9(7):1543.

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  5. Van Daele R, Brüggemann RJ, Dreesen E, Depuydt P, Rijnders B, Cotton F, Fage D, Gijsen M, Van Zwam K, Debaveye Y, et al. Pharmacokinetics and target attainment of intravenous posaconazole in critically ill patients during extracorporeal membrane oxygenation. J Antimicrob Chemother. 2021;76(5):1234–41.

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The authors would like to thank Cato Jacobs and Matthias Gijsen for their data collection support.

This research received no external funding.

Author notes

  1. Ruth Van Daele and Isabel Spriet are shared last author

Authors and Affiliations

  1. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium

    Beatrijs Mertens, Ruth Van Daele & Isabel Spriet

  2. Pharmacy Department, University Hospitals Leuven, Leuven, Belgium

    Beatrijs Mertens, Ruth Van Daele & Isabel Spriet

  3. Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium

    Joost Wauters

  4. Medical Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium

    Joost Wauters & Greet Hermans

  5. Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

    Yves Debaveye & Greet Hermans

  6. Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium

    Yves Debaveye

  7. Department of Intensive Care Medicine, Ziekenhuis Netwerk Antwerpen, ZNA Stuivenberg, Antwerp, Belgium

    Niels Van Regenmortel

  8. Department of Perfusion Technology, University Hospitals Leuven, Leuven, Belgium

    Karlien Degezelle

  9. Department of General Internal Medicine, Medical Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium

    Philippe Meersseman

  10. Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium

    Christophe Vandenbriele

  11. Department of Adult Intensive Care, Royal Brompton & Harefield NHS Foundation Trust, London, UK

    Christophe Vandenbriele

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Contributions

Conceptualization: BM, RVD, IS; methodology: BM, RVD, IS; investigation: BM, JW, YD, NVR, KD, PM, GH, CVDB, RVD, IS; Analysis: BM, RVD, IS; writing—original draft: BM, RVD, IS; writing—review and editing: JW, YD, NVR, KD, PM, GH, CVDB. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Beatrijs Mertens.

Ethics approval and consent to participate

The study was approved by the Ethics Committee Research UZ/KU Leuven (S65215). Not applicable.

Consent for publication

Not applicable.

Competing interests

JW reports investigator-initiated grants from Pfizer, Gilead and MSD; consulting fees from Pfizer and Gilead; speakers’ fees from Pfizer, Gilead and MSD; travel fees from Pfizer, Gilead and MSD; participation in advisory boards of Pfizer and Gilead; receipt of study drugs from MSD, outside the submitted work. YD reports speakers’ and travel fees from Pfizer and participation in advisory boards of Pfizer, outside the submitted work. GH is supported by the Flanders Research Foundation (FWO Vlaanderen) through a senior clinical research fellowship. IS is supported by the Clinical Research Fund of UZ Leuven and reports consulting fees from Pfizer and Cidara; speakers’ fees from Pfizer; travel fees from Pfizer, outside the submitted work. BM, NVR, KD, PM, CVDB and RVD have no conflicts of interest to declare related to this work.

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Additional file 1.

file 1: Baseline characteristics of patients included in the retrospective analysis of isavuconazole trough concentrations during extracorporeal membrane oxygenation (n= 4). file 2: Ratio of isavuconazole trough concentrations to isavuconazole daily doses for patients concomitantly treated with isavuconazole and extracorporeal membrane oxygenation (n= 4).

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Mertens, B., Wauters, J., Debaveye, Y. et al. The impact of extracorporeal membrane oxygenation on the exposure to isavuconazole: a plea for thorough pharmacokinetic evaluation. Crit Care 26, 227 (2022). https://doi.org/10.1186/s13054-022-04093-y

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Keywords

  • Extracorporeal membrane oxygenation
  • Azoles
  • Isavuconazole
  • Pharmacokinetics
  • Therapeutic drug monitoring

中文翻译：
体外膜氧合对艾沙康唑暴露的影响：呼吁进行彻底的药代动力学评估

体外膜肺氧合 (ECMO) 越来越多地用于为危及生命的呼吸和/或心力衰竭患者提供临时（心脏）肺支持，包括患有流感和冠状病毒病 2019 (COVID-19) 相关的急性呼吸道疾病的危重患者窘迫综合征。由于病理生理学改变（例如，体液转移、低白蛋白血症、肾功能不全和肾清除率增加）和体外治疗，危重患者的抗菌药物药代动力学 (PK) 经常发生变化和变化。由于 ECMO 回路中回路启动的血液稀释和药物隔离，ECMO 可能会显着影响药物的 PK。ECMO对具有霉菌活性的三唑类药物PK的影响，例如伏立康唑和艾沙康唑，已变得越来越重要，因为它们被推荐为流感和 COVID-19 相关肺曲霉病的（一线）抗真菌疗法。基于艾沙康唑的高亲脂性和广泛的血浆蛋白结合，理论上三唑易于吸附到 ECMO 回路并随后降低血浆浓度。迄今为止，ECMO 患者中艾沙康唑的暴露仅记录在两个病例报告和一个病例系列中（n  = 3)，其中建议 ECMO 期间血浆浓度降低 [1,2,3]。在本信函中，我们想强调的是，应谨慎解释 ECMO 导致艾沙康唑暴露量减少的建议，并且需要额外的研究来评估 ECMO 对艾沙康唑 PK 的独立影响。这与具有霉菌活性的三唑伏立康唑和泊沙康唑一致，体外研究和病例报告已建议将药物隔离到 ECMO 回路中。然而，ECMO 的独立作用无法在更大的回顾性 [4] 或前瞻性研究 [5] 中得到证实。

我们在此报告了艾沙康唑谷浓度 ( C min )，该浓度是在四名同时使用艾沙康唑和静脉-静脉 ECMO 治疗的危重患者的常规护理期间测量的（当地伦理委员会批准；S65215）。对于每位患者，ECMO 和艾沙康唑治疗的信息如图 1 所示。人口统计学和临床​​特征总结在附加文件 1 中。

图。1
图1

病例A、B、C、D的疗程。灰色阴影区域：体外膜氧合支持；分：艾沙康唑谷浓度（mg/L）；黑色短线：艾沙康唑日剂量（mg）；黑色水平虚线：艾沙康唑的最低谷浓度阈值为 1 mg/L，基于欧洲委员会对烟曲霉、黄曲霉和土曲霉的抗菌药敏试验断点；灰色垂直虚线：肺移植。C min：谷浓度；T x : 移植

全尺寸图片

在我们的案例系列中，艾沙康唑的暴露量变化很大，4 个C min低于 1 mg/L，可以提倡作为最低C min阈值，基于欧洲委员会对烟曲霉、黄曲霉的抗菌敏感性测试断点和A. terreus。多种因素可能导致艾沙康唑C min的变异性，包括给药剂量、治疗持续时间和治疗开始/剂量调整后达到稳定状态所需的时间。剂量校正的C min见附加文件 1：文件 2。C min在病例 A 和 B 中，表明在标准给药方案的 ECMO 支持期间可以实现足够的艾沙康唑暴露。在案例 A 中，通过增加 200 mg q12h 的维持剂量达到了 4.3 mg/L的C min 。考虑到艾沙康唑的线性 PK，可以假设 200 mg q24h 的标准剂量会导致C min  > 1 mg/L。在案例 B 中，这个最小目标C min是通过标准维持剂量实现的。相比之下，艾沙康唑C min在校正标准维持剂量 200 mg q24h 时，情况 C 和 D 未超过 1 mg/L 的目标。后者的结果与赵等人先前的报道一致。[3] 和米勒等人。[1]，其中记录了标准给药方案后的亚治疗暴露，并将其归因于 ECMO 。

不幸的是，根据之前发表的报告 [1,2,3] 和我们的病例系列，无法评估 ECMO 对重症患者艾沙康唑暴露的独立影响。因此，ECMO患者亚治疗性艾沙康唑暴露是由ECMO引起还是由危重疾病本身引起的关键问题仍未得到解答。这一证据差距强调了对危重​​患者进行大规模 PK 评估的必要性，包括肾清除率增加、低白蛋白血症、肝肾功能不全、肾替代治疗和 ECMO 的患者。在等待更多数据（例如， ICONIC 研究，ClinicalTrials.gov：NCT04777058）之前，有必要对 ECMO 和非 ECMO 患者的危重患者进行艾沙康唑的治疗药物监测。

可根据合理要求从相应作者处获得作为本手稿报告结果基础的个人参与者数据，前提是该要求在出版后符合当地伦理和研究治理标准。患者数据将被匿名化，研究文件将被编辑以保护参与者的隐私。

最小：_

谷浓度

体外膜肺氧合：

体外膜氧合

PK：

药代动力学

T x :

移植

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    文章谷歌学术

  2. Zurl C、Waller M、Schwameis F、Muhr T、Bauer N、Zollner-Schwetz I、Valentin T、Meinitzer A、Ullrich E、Wunsch S 等。艾沙康唑在侵袭性真菌感染混合患者队列中的治疗：艾沙康唑血浆浓度的结果、耐受性和临床意义。J真菌。2020 年；6(2):90。

    CAS 文章 谷歌学术

  3. 赵 Y，Seelhammer TG，巴雷托 EF，威尔逊 JW。在体外膜氧合期间改变脂质体两性霉素 B 和艾沙康唑的药代动力学和剂量。药物治疗。2020;40(1):89-95。

    CAS 文章 谷歌学术

  4. Van Daele R、Bekkers B、Lindfors M、Broman LM、Schauwvlieghe A、Rijnders B、Hunfeld NGM、Juffermans NP、Taccone FS、Coimbra Sousa CA 等。对接受体外膜肺氧合治疗的患者伏立康唑暴露的大型回顾性评估。微生物。2021;9(7):1543。

    文章谷歌学术

  5. Van Daele R、Brüggemann RJ、Dreesen E、Depuydt P、Rijnders B、Cotton F、Fage D、Gijsen M、Van Zwam K、Debaveye Y 等。体外膜肺氧合期间危重患者静脉注射泊沙康唑的药代动力学和达标。J Antimicrob Chemother。2021;76(5):1234-41。

    文章谷歌学术

下载参考资料

作者要感谢 Cato Jacobs 和 Matthias Gijsen 对数据收集的支持。

这项研究没有获得外部资助。

作者笔记

  1. Ruth Van Daele 和 Isabel Spriet 是最后一位作者

作者和附属机构

  1. 比利时鲁汶大学鲁汶大学制药和药理学系

    Beatrijs Mertens、Ruth Van Daele 和 Isabel Spriet

  2. 比利时鲁汶大学医院药学部

    Beatrijs Mertens、Ruth Van Daele 和 Isabel Spriet

  3. 微生物学、免疫学和移植系，KU Leuven，鲁汶，比利时

    约斯特·沃特斯

  4. 比利时鲁汶大学医院重症监护室

    Joost Wauters & Greet Hermans

  5. 细胞和分子医学系，KU Leuven，比利时鲁汶

    Yves Debaveye 和 Greet Hermans

  6. 比利时鲁汶大学医院重症监护室

    伊夫·德巴维耶

  7. 重症监护医学部，Ziekenhuis Netwerk Antwerpen，ZNA Stuivenberg，安特卫普，比利时

    尼尔斯·范·雷根莫特尔

  8. 比利时鲁汶大学医院灌注技术系

    卡利安·德格泽勒

  9. 比利时鲁汶大学医院内科、重症监护室普通内科

    菲利普·梅尔斯曼

  10. 比利时鲁汶大学医院心血管疾病系

    克里斯托夫·范登布里勒

  11. 英国伦敦皇家 Brompton & Harefield NHS 信托基金成人重症监护部

    克里斯托夫·范登布里勒

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贡献

概念化：BM、RVD、IS；方法学：BM、RVD、IS；调查：BM、JW、YD、NVR、KD、PM、GH、CVDB、RVD、IS；分析：BM、RVD、IS；写作——原稿：BM、RVD、IS；写作——评论和编辑：JW、YD、NVR、KD、PM、GH、CVDB。所有作者阅读并认可的终稿。

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与 Beatrijs Mertens 的通信。

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该研究得到了伦理委员会研究 UZ/KU Leuven (S65215) 的批准。不适用。

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不适用。

利益争夺

JW 报告了辉瑞、吉利德和默沙东的研究人员发起的资助；辉瑞和吉利德的咨询费；辉瑞、吉利德和默沙东的演讲者费用；辉瑞、吉利德和默沙东的差旅费；参与辉瑞和吉利德的顾问委员会；在提交的工作之外收到来自 MSD 的研究药物。YD 报告了辉瑞公司的演讲者和差旅费，以及在提交的工作之外参与辉瑞公司咨询委员会的费用。GH 由法兰德斯研究基金会 (FWO Vlaanderen) 通过高级临床研究奖学金获得支持。IS 得到 UZ Leuven 临床研究基金的支持，报告辉瑞和 Cidara 的咨询费用；辉瑞的演讲者费用；辉瑞公司的差旅费，在提交的工作之外。BM、NVR、KD、PM、CVDB 和 RVD 没有与此工作相关的利益冲突声明。

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附加文件 1。

文件 1：体外膜氧合期间艾沙康唑谷浓度的回顾性分析中包括的患者的基线特征（n = 4）。文件 2：同时接受艾沙康唑和体外膜肺氧合治疗的患者，艾沙康唑谷浓度与艾沙康唑日剂量之比（n=4）。

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Mertens, B.、Wauters, J.、Debaveye, Y.等人。体外膜氧合对艾沙康唑暴露的影响：呼吁进行彻底的药代动力学评估。重症监护 26, 227 (2022)。https://doi.org/10.1186/s13054-022-04093-y

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关键词

  • 体外膜氧合
  • 唑类
  • 艾沙康唑
  • 药代动力学
  • 治疗药物监测
更新日期：2022-07-27
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