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Cefiderocol Dosing for Patients Receiving Continuous Renal Replacement Therapy
Clinical Pharmacology & Therapeutics ( IF 6.3 ) Pub Date : 2022-07-06 , DOI: 10.1002/cpt.2703
Xiaohui Wei 1 , Shabnam Naseer 2 , Edward A Weinstein 2, 3 , Dmitri Iarikov 2 , Sumathi Nambiar 2, 4 , Kellie S Reynolds 1 , Seong H Jang 1, 5
Affiliation  

In this report, we describe our scientific approach for including effluent flow rate (QE)–based dosing recommendations of cefiderocol for patients receiving continuous renal replacement therapy (CRRT) in the product labeling. The total clearance (CL) of cefiderocol in patients receiving CRRT was estimated as the sum of patients’ nonrenal clearance (CLnonrenal) and extracorporeal clearance by CRRT (CLCRRT), based on the following rationale: (a) The renal clearance (CLrenal) of cefiderocol is assumed to be negligible in patients receiving CRRT, (b) CLnonrenal represents the CRRT patients’ own remaining systemic clearance and is estimated from the observed clearance in participants with creatinine clearance (CLcr) < 15 mL/minute without undergoing hemodialysis, and (c) CLCRRT was estimated by the product of unbound (free) fraction of plasma drug concentration (fu) and QE because the free fraction of low-molecular-weight compounds like cefiderocol (752 Da) can be completely filtered by CRRT, regardless of CRRT modality. Hence, cefiderocol CL in CRRT patients was calculated by the equation of CL = CLnonrenal + fu × QE. Accordingly, the cefiderocol dosing regimens for patients receiving CRRT in clinically relevant ranges of QE were determined with the goal of achieving an average daily area under the concentration-time curve (AUC) observed in patients not receiving CRRT. Subsequently, pharmacokinetic (PK) simulations demonstrated that cefiderocol PK profiles following the QE-based dosing in patients receiving CRRT would be similar to those in patients not receiving CRRT.

中文翻译:


接受连续肾脏替代治疗的患者的头孢地洛剂量



在本报告中,我们描述了我们的科学方法,将基于流出物流速 ( Q E ) 的头孢地考剂量建议纳入产品标签中,用于接受连续肾脏替代治疗 (CRRT) 的患者。接受 CRRT 的患者中头孢地罗总清除率 (CL) 估计为患者的非肾清除率 (CL nonrenal ) 和 CRRT 的体外清除率 (CL CRRT ) 之和,基于以下基本原理: (a) 肾清除率 (CL nonrenal )假定接受 CRRT 的患者中头孢地洛考的清除率可以忽略不计,(b) CL非肾表示 CRRT 患者自身的剩余全身清除率,并根据肌酐清除率 (CLcr) < 15 mL/分钟且未接受治疗的参与者中观察到的清除率进行估计(c) CL CRRT通过血浆药物浓度的未结合(游离)分数 ( fu ) 和Q E 的乘积来估计,因为低分子量化合物如头孢地洛考 (752 Da) 的游离分数可以完全无论 CRRT 模式如何,均由 CRRT 过滤。因此,CRRT 患者的头孢地罗 CL 计算公式为 CL = CL非肾性+ f u × Q E 。因此,在临床相关Q E范围内接受 CRRT 的患者的头孢地罗给药方案确定,目标是实现在未接受 CRRT 的患者中观察到的平均每日浓度-时间曲线下面积 (AUC)。 随后,药代动力学 (PK) 模拟表明,接受 CRRT 的患者在基于Q E给药后的头孢地罗 PK 曲线与未接受 CRRT 的患者相似。
更新日期:2022-07-06
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