Edoxaban pharmacokinetics during in vitro continuous renal replacement therapy.

IF 2.2 4区 医学 Q2 UROLOGY & NEPHROLOGY BMC Nephrology Pub Date : 2024-10-10 DOI:10.1186/s12882-024-03777-7
Eric Wenzler, Kaitlyn Dalton, Lauren Andrews, Scott T Benken
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Abstract

Background: To evaluate the clearance of edoxaban during modeled in vitro continuous renal replacement therapy (CRRT), assess protein binding and circuit adsorption, and provide initial dosing recommendations.

Methods: Edoxaban was added to the CRRT circuit and serial pre-filter bovine blood samples were collected along with post-filter blood and effluent samples. All experiments were performed in duplicate using continuous veno-venous hemofiltration (CVVH) and hemodialysis (CVVHD) modes, with varying filter types, flow rates, and point of CVVH replacement fluid dilution. Concentrations of edoxaban and urea were quantified via liquid chromatography-tandem mass spectrometry. Plasma pharmacokinetic parameters for edoxaban were estimated via noncompartmental analysis. Two and three-way analysis of variance (ANOVA) models were built to assess the effects of mode, filter type, flow rate, and point of dilution on CLCRRT. Linear regression was utilized to provide dosing estimations across CRRT effluent flow rates from 0.5 to 5 L/h. Optimal edoxaban doses were suggested using CLCRRT and population non-renal clearance (CLNR) to estimate total clearance and match the systemic AUC associated with efficacy in the treatment of venous thromboembolism.

Results: Edoxaban clearance from the CRRT circuit occurred primarily via hemofilter adsorption to the HF1400 and M150 filters at 74% and 65%, respectively, while mean percent protein binding was 41%. Multivariate analyses confirmed the lack of influence of CRRT mode, filter type, and point of dilution on the CLCRRT of edoxaban allowing dosing recommendations to be made based on effluent flow rate. Edoxaban doses of 30-45 mg once daily were estimated to achieve target the AUC threshold for flow rates from 0.5 to 5 L/h.

Conclusion: For CRRT flow rates most employed in clinical practice, an edoxaban dose of 45 mg once daily is predicted to achieve target systemic exposure thresholds for venous thromboembolism treatment. The safety and efficacy of this proposed dosing warrants further investigation in clinical studies.

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体外连续肾脏替代疗法中的埃多沙班药代动力学。
背景:评估体外连续性肾脏替代疗法(CRRT)中埃多沙班的清除率目的:评估埃多沙班在体外连续肾脏替代疗法(CRRT)模型中的清除率,评估蛋白结合和回路吸附,并提供初始剂量建议:将埃多沙班添加到 CRRT 回路中,收集一系列滤过前牛血样以及滤过后血液和流出物样本。所有实验均采用连续静脉血液滤过(CVVH)和血液透析(CVVHD)模式,以不同的过滤器类型、流速和 CVVH 置换液稀释点重复进行。埃多沙班和尿素的浓度通过液相色谱-串联质谱法进行定量。通过非室分析估算埃多沙班的血浆药代动力学参数。建立了二元和三元方差分析 (ANOVA) 模型,以评估模式、过滤器类型、流速和稀释点对 CLCRRT 的影响。利用线性回归对 0.5 至 5 升/小时的 CRRT 流出流速进行剂量估算。利用 CLCRRT 和人群非肾清除率(CLNR)估算总清除率,并与治疗静脉血栓栓塞疗效相关的全身 AUC 相匹配,提出了最佳的埃多沙班剂量建议:CRRT回路中的埃多沙班清除率主要是通过HF1400和M150过滤器的血液滤过吸附实现的,分别为74%和65%,而平均蛋白结合率为41%。多变量分析证实,CRRT 模式、过滤器类型和稀释点对埃多沙班的 CLCRRT 没有影响,因此可以根据流出流速提出剂量建议。据估计,每天一次 30-45 毫克的埃多沙班剂量可使 0.5 至 5 升/小时的流速达到目标 AUC 临界值:结论:对于临床实践中最常用的 CRRT 流速,每天一次 45 毫克的埃多沙班剂量可达到静脉血栓栓塞治疗的目标全身暴露阈值。这一建议剂量的安全性和有效性值得在临床研究中进一步探讨。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
BMC Nephrology
BMC Nephrology UROLOGY & NEPHROLOGY-
CiteScore
4.30
自引率
0.00%
发文量
375
审稿时长
3-8 weeks
期刊介绍: BMC Nephrology is an open access journal publishing original peer-reviewed research articles in all aspects of the prevention, diagnosis and management of kidney and associated disorders, as well as related molecular genetics, pathophysiology, and epidemiology.
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