Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, Centre Hospitalier Universitaire (CHU) Nîmes, Nîmes.
Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Univ Montpellier.
Ther Drug Monit. 2021 Dec 1;43(6):747-755. doi: 10.1097/FTD.0000000000000874.
In this study, the authors aimed to compare the pharmacokinetics (PK) of micafungin in critically ill patients receiving continuous venovenous hemofiltration (CVVH, 30 mL·kg-1·h-1) with those of patients receiving equidoses of hemodiafiltration (CVVHDF, 15 mL·kg-1·h-1 + 15 mL·kg-1·h-1) and determine the optimal dosing regimen using the developed model.
Patients with septic shock undergoing continuous renal replacement therapy and receiving a conventional dose of 100 mg micafungin once daily were eligible for inclusion. Total micafungin plasma concentrations from 8 CVVH sessions and 8 CVVHDF sessions were subjected to a population PK analysis using Pmetrics. Validation of the model performance was reinforced by external validation. Monte Carlo simulations were performed considering the total ratio of free drug area under the curve (AUC) over 24 hours to the minimum inhibitory concentration (MIC) (AUC0-24/MIC) in plasma.
The median total body weight (min-max) was 94.8 (66-138) kg. Micafungin concentrations were best described by a 2-compartmental PK model. No covariates, including continuous renal replacement therapy modality (CVVH or CVVHDF), were retained in the final model. The mean parameter estimates (SD) were 0.96 (0.32) L/h for clearance and 14.8 (5.3) L for the central compartment volume. External validation confirmed the performance of the developed PK model. Dosing simulations did not support the use of standard 100 mg daily dosing, except for Candida albicans on the second day of therapy. A loading dose of 150 mg followed by 100 mg daily reached the probability of target attainment for all C. albicans and C. glabrata, but not for C. krusei and C. parapsilosis.
No difference was observed in micafungin PK between equidoses of CVVH and CVVHDF. A loading dose of 150 mg is required to achieve the PK/PD target for less susceptible Candida species from the first day of therapy.
在这项研究中，作者旨在比较接受连续静脉-静脉血液滤过（CVVH，30mL·kg-1·h-1）的危重症患者与接受等剂量血液透析滤过（CVVHDF，15mL·kg-1·h-1 + 15mL·kg-1·h-1）的患者米卡芬净的药代动力学（PK），并使用所建立的模型确定最佳给药方案。
纳入接受常规剂量 100mg 米卡芬净每日一次且正在接受连续肾脏替代治疗的脓毒症休克患者。使用 Pmetrics 对 8 个 CVVH 疗程和 8 个 CVVHDF 疗程的米卡芬净总血浆浓度进行群体 PK 分析。通过外部验证加强模型性能的验证。考虑到总游离药物 AUC0-24 与血浆中最低抑菌浓度（MIC）的比值（AUC0-24/MIC），进行蒙特卡罗模拟。
中位总体重（最小-最大）为 94.8（66-138）kg。米卡芬净浓度最好由 2 室 PK 模型描述。最终模型中未保留任何协变量，包括连续肾脏替代治疗方式（CVVH 或 CVVHDF）。平均参数估计值（SD）为清除率 0.96（0.32）L/h 和中央室容积 14.8（5.3）L。外部验证证实了所建立的 PK 模型的性能。除治疗第二天的白色念珠菌外，剂量模拟不支持使用标准的 100mg 每日剂量。150mg 负荷剂量加 100mg 每日剂量可达到所有白色念珠菌和光滑念珠菌的目标达标概率，但对克柔念珠菌和近平滑念珠菌无效。
CVVH 和 CVVHDF 之间米卡芬净 PK 无差异。从治疗第一天开始，需要 150mg 的负荷剂量才能达到对较不敏感的念珠菌种的 PK/PD 目标。
