体外膜肺氧合技术对重症患者体内达托霉素药代药效学的影响

doi:10.12092/j.issn.1009-2501.2022.01.006

中国临床药理学与治疗学 ›› 2022, Vol. 27 ›› Issue (1): 39-46.doi: 10.12092/j.issn.1009-2501.2022.01.006

体外膜肺氧合技术对重症患者体内达托霉素药代药效学的影响

胡琳璘^1,2，徐思露³，厉伟兰²，何杰²，张锦璐⁴，邵华²

¹东南大学附属中大医院临床试验机构办公室，南京 210009，江苏；²东南大学附属中大医院药学部，南京 210009，江苏；³江苏省肿瘤医院药学部，南京 210009，江苏；⁴东南大学医学院，南京 210009，江苏

收稿日期:2021-09-26 修回日期:2021-12-31 出版日期:2022-01-26 发布日期:2022-02-09
通讯作者: 邵华，女，博士，主任药师，主要从事临床药学、医院药学管理工作研究。 Tel: 025-83272127 E-mail: 369594546@qq.com
作者简介:胡琳璘，女，博士，副主任药师，主要从事治疗药物监测、Ⅰ期临床试验研究相关工作。 Tel: 025-83272127 E-mail: eliza50@sina.com
基金资助:
国家自然科学基金（81503340）；南京药学会-常州四药医院药学科研基金（2019YX012）；江苏省药学会-奥赛康科研基金（A201904）

Effects of extracorporeal membrane oxygenation on pharmacokinetics and pharmacodynamics of daptomycin in critically ill patients

HU Linlin1,2, XU Silu3, LI Weilan2, HE Jie2, ZHANG Jinglu4, SHAO Hua2

¹Office of Clinical Trial Institution, Nanjing Zhongda Hospital, Southeast University, School of Medicine, Nanjing 210009, Jiangsu, China

Received:2021-09-26 Revised:2021-12-31 Online:2022-01-26 Published:2022-02-09

摘要/Abstract

摘要： 目的：探讨体外膜肺氧合治疗（ECMO）对重症感染患者达托霉素药动学/药效学（PK/PD）的影响。方法：入选24位重症感染患者其中ECMO组和非ECMO组各12例，静脉滴注达托霉素500 mg qd，待药物达稳后于不同时间点采集静脉血，测定血药浓度，计算并比较组间药代动力学参数，使用蒙特卡罗模拟评估达托霉素相同给药剂量下在不同人群中的靶向达成概率（PTA），通过应用耐甲氧西林金黄色葡萄球菌（MRSA）的达托霉素MIC分布计算累积反应分数（CFR）。结果：ECMO与非ECMO组患者静滴达托霉素500 mg qd后，Cmax分别为（85.5±25.4） μg/mL和（79.4±29.2） μg/mL，AUC0-24分别为（674.2±267.2） mg·L-1·h和（952.9±304.5） mg·L-1·h，t1/2分别为（10.9±2.1） h和（11.6±4.3） h，Vd为（0.21±0.12） L/kg和（0.150±0.061） L/kg，CL为（13.3±4.7） mL·h-1·kg-1和（9.2±3.4） mL·h-1·kg-1，AUC0-24和CL在两组间存在显著性差异，增加其余各药动学参数无显著性差异。蒙特卡洛模拟结果表明，当MRSA对达托霉素敏感性下降时（MIC≥1 mg/L），ECMO组PTA值和CFR值均小于90%。结论：体外膜肺氧合装置会在一定程度上影响达托霉素于重症感染患者体内的药代动力学特征。对于绝大多数行ECMO重症患者来说，当MIC≥1 mg/mL时，标准给药剂量的达托霉素无法有效覆盖MRSA所致感染，需要增加给药剂量以保证达托霉素CFR>90%。另外，建议此类患者实施达托霉素的治疗药物浓度监测，同时临床上应根据MRSA病原菌对药物的敏感性调整给药方案结论。

关键词: 达托霉素, 重症感染, 体外膜肺氧合技术, 药代-药效动力学

Abstract: AIM: To investigate the effect of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics/pharmacodynamics (PK/PD) of daptomycin in critically ill patients. METHODS: Twenty four patients with severe infection in our hospital were randomly selected and divided into ECMO group and non ECMO group. They were intravenously injected with daptomycin 500 mg qd. After the drug reached the stability statement, venous blood was collected at different time points before and after the infusion. The plasma drug concentration was measured and the pharmacokinetic parameters were calculated. The probability target acquisition (PTA) and the cumulative fraction response (CFR) were calculated by Monte Carlo simulation. RESULTS: After dosing, the main pharmacokinetic parameters in ECMO and non-ECMO group were calculated and listed as follows: Cmax were (85.5±25.4) μg/mL and (79.4±29.2) μg/mL, AUC0-24 were (674.2±267.2) mg·L-1·h and (952.9±304.5) mg·L-1·h，t1/2 were (10.9±2.1) h and (11.6±4.3) h，Vd were (0.21±0.12) L/kg and (0.150±0.061) L/kg，CL were (13.3±4.7) mL·h-1·kg-1 and (9.2±3.4) mL·h-1·kg-1. There were significant differences in AUC0-24 and CL between the two groups, and there was no significant difference in other pharmacokinetic parameters. Monte Carlo simulation results showed that when the sensitivity of MRSA to daptomycin decreased (MIC≥1 mg/L), the PTA values of ECMO group, non-ECMO group and healthy volunteers were less than 90%. CONCLUSION: ECMO may affect the PK/PD of daptomycin in patients with severe infection to a certain extent. When MIC≥1 mg/L, it is recommended to increase the dosage to achieve the expected antibacterial effect. In view of the individual differences of daptomycin in patients with ECMO, therapeutic drug monitoring (TDM) should be implemented in these patients, and the administration scheme should be adjusted according to the sensitivity of MRSA pathogens to drugs.

Key words: daptomycin, severe infection, the extracorporeal membrane oxygenation, the PK-PD study

中图分类号:

R969

胡琳璘, 徐思露, 厉伟兰, 何杰, 张锦璐, 邵华. 体外膜肺氧合技术对重症患者体内达托霉素药代药效学的影响[J]. 中国临床药理学与治疗学, 2022, 27(1): 39-46.

HU Linlin, XU Silu, LI Weilan, HE Jie, ZHANG Jinglu, SHAO Hua. Effects of extracorporeal membrane oxygenation on pharmacokinetics and pharmacodynamics of daptomycin in critically ill patients[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2022, 27(1): 39-46.

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[2]	范晓, 赫留党, 徐杨. 谷氨酰胺对肠穿孔重症感染模型的治疗作用[J]. 中国临床药理学与治疗学, 2010, 15(4): 410-415.

体外膜肺氧合技术对重症患者体内达托霉素药代药效学的影响

Effects of extracorporeal membrane oxygenation on pharmacokinetics and pharmacodynamics of daptomycin in critically ill patients

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