Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Room 164 (M/C 886), Chicago, IL, 60612, USA.
Clinical Pharmacology and Pharmacokinetics, Shionogi & Co., Ltd., Osaka, Japan.
Clin Pharmacokinet. 2022 Apr;61(4):539-552. doi: 10.1007/s40262-021-01086-y. Epub 2021 Nov 18.
The need for continuous renal replacement therapy (CRRT) in critically ill patients with serious infections is associated with clinical failure, emergence of resistance, and excess mortality. These poor outcomes are attributable in large part to subtherapeutic antimicrobial exposure and failure to achieve target pharmacokinetic/pharmacodynamic (PK/PD) thresholds during CRRT. Cefiderocol is a novel siderophore cephalosporin with broad in vitro activity against resistant pathogens and is often used to treat critically ill patients, including those receiving CRRT, despite the lack of data to guide dosing in this population.
The aim of this study was to evaluate the PK and PD of cefiderocol during in vitro and in vivo CRRT and provide optimal dosing recommendations.
The PK and dialytic clearance of cefiderocol was evaluated via an established in vitro CRRT model across various modes, filter types, and effluent flow rates. These data were combined with in vivo PK data from nine patients receiving cefiderocol while receiving CRRT from phase III clinical trials. Optimal dosing regimens and their respective probability of target attainment (PTA) were assessed via an established population PK model with Bayesian estimation and 1000-subject Monte Carlo simulations at each effluent flow rate.
The overall mean sieving/saturation coefficient during in vitro CRRT was 0.90 across all modes, filter types, effluent flow rates, and points of replacement fluid dilution tested. Adsorption was negligible at 10.9%. Three-way analysis of variance (ANOVA) and multiple linear regression analyses demonstrated that effluent flow rate is the primary driver of clearance during CRRT and can be used to calculate optimal cefiderocol doses required to match the systemic exposure observed in patients with normal renal function. Bayesian estimation of these effluent flow rate-based optimal doses in nine patients receiving CRRT from the phase III clinical trials of cefiderocol revealed comparable mean (± standard deviation) area under the concentration-time curve values as patients with normal renal function (1709 ± 539 mg·h/L vs. 1494 ± 58.4 mg·h/L; p = 0.26). Monte Carlo simulations confirmed these doses achieved >90% PTA against minimum inhibitory concentrations ≤4 mg/L at effluent flow rates from 0.5 to 5 L/h.
The optimal dosing regimens developed from this work have been incorporated into the prescribing information for cefiderocol, making it the first and only antimicrobial with labeled dosing for CRRT. Future clinical studies are warranted to confirm the efficacy and safety of these regimens.
严重感染的危重症患者需要持续肾脏替代治疗（CRRT），这与临床治疗失败、耐药性出现和死亡率过高有关。这些不良结果在很大程度上归因于治疗药物暴露量低于最低有效治疗浓度（subtherapeutic antimicrobial exposure），以及在 CRRT 过程中未能达到目标药代动力学/药效学（PK/PD）阈值。头孢地尔是一种新型的铁载体头孢菌素，对耐药病原体具有广泛的体外活性，常用于治疗危重症患者，包括正在接受 CRRT 的患者，尽管缺乏指导此类人群用药的相关数据。
本研究旨在评估头孢地尔在体外和体内 CRRT 中的药代动力学（PK）和药效学（PD），并提供最佳的给药建议。
通过建立的体外 CRRT 模型，在不同模式、滤器类型和流出液流速下评估头孢地尔的 PK 和透析清除率。将这些数据与来自三项 III 期临床试验的 9 名接受头孢地尔治疗且同时接受 CRRT 的患者的体内 PK 数据相结合。通过建立的群体 PK 模型进行贝叶斯估计和 1000 个主体蒙特卡罗模拟，评估了在每个流出液流速下的最佳给药方案及其各自的目标达标率（probability of target attainment，PTA）。
在整个体外 CRRT 过程中，头孢地尔的平均筛系数/饱和度系数为 0.90，适用于所有模式、滤器类型、流出液流速和替换液稀释点。吸附率可忽略不计（10.9%）。三因素方差分析（analysis of variance，ANOVA）和多元线性回归分析表明，流出液流速是 CRRT 中清除率的主要驱动因素，可用于计算出匹配肾功能正常患者观察到的系统暴露所需的最佳头孢地尔剂量。对来自头孢地尔 III 期临床试验的 9 名接受 CRRT 的患者进行的贝叶斯估计这些基于流出液流速的最佳剂量的分析表明，与肾功能正常的患者相比，其平均（±标准差）浓度-时间曲线下面积（area under the concentration-time curve，AUC）值相似（1709±539 mg·h/L vs. 1494±58.4 mg·h/L；p=0.26）。蒙特卡罗模拟证实，这些剂量在 0.5 至 5 L/h 的流出液流速下可达到对最小抑菌浓度（minimum inhibitory concentration，MIC）≤4 mg/L 的>90% PTA。
本研究开发的最佳给药方案已被纳入头孢地尔的说明书，使其成为第一个也是唯一一个具有 CRRT 标签剂量的抗菌药物。需要开展进一步的临床研究来确认这些方案的疗效和安全性。
