重症侵袭性真菌感染患者两性霉素B的药代动力学变化及其影响因素分析

中国真菌学杂志　 2023, Vol. 18 　Issue (2): 117-122.

重症侵袭性真菌感染患者两性霉素B的药代动力学变化及其影响因素分析

王皓飞^1,2, 王金龙^1,2, 胡文瀚^1,2, 宋倩文^1,2, 吴昌德^1,2, 何洁³, 胡琳璘³, 徐静媛^1,2, 李卿^1,2, 潘纯^1,2, 谢剑锋^1,2, 黄英姿^1,2

1. 东南大学附属中大医院重症医学科, 南京 210009;
2. 江苏省重症医学重点实验室, 南京 210009;
3. 东南大学附属中大医院药学部, 南京 210009

收稿日期:2022-10-31 出版日期:2023-04-28 发布日期:2023-05-26
通讯作者: 黄英姿,E-mail:yz_huang@126.com E-mail:yz_huang@126.com
作者简介:王皓飞,男(汉族),硕士.E-mail:seu_wanghaofei@163.com
基金资助:
江苏省重点研发计划(社会发展)项目(BE2021734)

Pharmacokinetic changes and influencing factors of amphotericin B in patients with severe invasive fungal infection

WANG Haofei^1,2, WANG Jinlong^1,2, HU Wenhan^1,2, SONG Qianwen^1,2, WU Changde^1,2, HE Jie³, HU Linlin³, XU Jingyuan^1,2, LI Qing^1,2, PAN Chun^1,2, XIE Jianfeng^1,2, HUANG Yingzi^1,2

1. Department of Critical Care Medicine, Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, China;
2. Jiangsu Provincial Key Laboratory of Critical Care Medicine, Southeast University, Nanjing 210009, China;
3. Department of Pharmacy, Zhongda Hospital Affiliated to Southeast University, Nanjing 210009, China

Received:2022-10-31 Online:2023-04-28 Published:2023-05-26

摘要/Abstract

摘要： 目的探讨脱氧胆酸盐两性霉素B在重症侵袭性真菌感染患者体内药代动力学(pharmacokinetics,PK)特点及目标靶值并分析其PK变化的影响因素。方法选取从2018年11月—2022年11月在东南大学附属中大医院重症医学科就诊并接受脱氧胆酸盐两性霉素B输入治疗的重症侵袭性真菌病患者。用药从1 mg/d开始逐渐累加至50 mg/d,持续静脉泵入6 h,在用药第7、14天采集给药前及给药后1、3、6、9、12 h的外周血2 mL,采用液相色谱与串联质谱联用(liquid chromatography tandem mass spectrometry, LC-MS/MS)法测定血浆中两性霉素 B 的浓度。观察两性霉素B的PK特点并采用线性回归法,分析影响其PK变化的影响因素。结果共纳入12例重症侵袭性真菌病患者,对比正常受试者中得到的脱氧胆酸盐两性霉素B的药代动力学参数,重症侵袭性真菌感染(invasive fungal infection, IFI)患者体内两性霉素B的谷浓度(Cmin)、清除率(clearance, CL)、半衰期(t_1/2)和浓度时间曲线下面积(area under concentration-time curve, AUC)均高于健康受试者(均P＜0.05),而血药浓度峰值(Cmax)(1.63±0.77)mg/L未见明显差异。更快的两性霉素B剂量累加速度相比于正常累加组无明显的不良反应发生率(均P＞0.05)变化,并且其Cmax和表观分布容积(apparent volume of distribution, Vd)更高。单因素分析显示实时APACHEⅡ评分可能是两性霉素B峰浓度的影响因素(P=0.008)。结论重症IFI患者体内两性霉素B的谷浓度、CL、半衰期(t_1/2)、和AUC均高于健康受试者,但Cmax两组未见明显差异,实时APACHEⅡ评分可能是影响两性霉素B峰浓度的影响因素。更快的两性霉素B药物累加速度未表现出明显的即刻不良反应发生率的增加,并且存在更高的药效浓度。

关键词: 两性霉素B, 侵袭性真菌感染, 药物代谢动力学, 重症患者

Abstract: Objective To investigate the PK characteristics and target value of deoxycholate amphotericin B in patients with severe invasive fungal infection and analyze the influencing factors of PK changes. Methods Patients with severe invasive fungal disease who were admitted to the Department of Critical Care Medicine of Zhongda Hospital Affiliated to Southeast University from November 2018 to November 2022 and received deoxycholate amphotericin B infusion therapy were selected. Amphotericin B was gradually accumulated from 1 mg/d to 50 mg/d, and was continuously pumped intravenously for 6 h. On the 7th and 14th day of administration, 2 mL of peripheral blood was collected every time before administration and at 1, 3,6,9 and 12 h after administration. The concentration of amphotericin B in plasma was determined by LC-MS/MS method. The PK characteristics of amphotericin B were observed and the influencing factors of PK changes were analyzed by linear regression method. Results A total of 12 patients with severe invasive fungal disease were included. Compared with the pharmacokinetic parameters of deoxycholate amphotericin B obtained in normal subjects, the trough concentration, CL, half-life (t_1/2), and AUC of amphotericin B in severe IFI patients were higher than those in healthy subjects (all P＜0.05 ), and its Cmax and Vd were higher. Univariate analysis showed that real-time APACHE II score may be the influencing factor of amphotericin B peak concentration (P=0.008). Conclusion The trough concentration, CL, half-life (t_1/2) and AUC of amphotericin B in patients with severe IFI were higher than those in healthy subjects, but there was no significant difference in Cmax between the two groups. Real-time APACHE II score might be the influencing factor of amphotericin B peak concentration. The faster cumulative acceleration of amphotericin B did not show a significant increase in the incidence of immediate adverse reactions, and there was a higher pharmacodynamic concentration.

Key words: amphotericin B, invasive fungal infection, pharmacokinetics, critical care patient

中图分类号:

R519
R978.5

王皓飞, 王金龙, 胡文瀚, 宋倩文, 吴昌德, 何洁, 胡琳璘, 徐静媛, 李卿, 潘纯, 谢剑锋, 黄英姿. 重症侵袭性真菌感染患者两性霉素B的药代动力学变化及其影响因素分析[J]. 中国真菌学杂志, 2023, 18(2): 117-122.

WANG Haofei, WANG Jinlong, HU Wenhan, SONG Qianwen, WU Changde, HE Jie, HU Linlin, XU Jingyuan, LI Qing, PAN Chun, XIE Jianfeng, HUANG Yingzi. Pharmacokinetic changes and influencing factors of amphotericin B in patients with severe invasive fungal infection[J]. Chinese Journal of Mycology, 2023, 18(2): 117-122.

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