处理延迟或漏服直接口服抗凝剂的剂量:基于模型的个体化补救剂量。

Handling delayed or missed direct oral anticoagulant doses: model-informed individual remedial dosing.

机构信息

Department of Pharmacy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA.

出版信息

Blood Adv. 2024 Nov 26;8(22):5906-5916. doi: 10.1182/bloodadvances.2024013854.

Abstract

Nonadherence to direct oral anticoagulant (DOAC) pharmacotherapy may increase the risk of thromboembolism or bleeding, and delayed or missed doses are the most common types of nonadherence. Current recommendations from regulatory agencies or guidelines regarding this issue lack evidence and fail to consider individual differences. This study aimed to develop individual remedial dosing strategies when the dose was delayed or missed for DOACs, including rivaroxaban, apixaban, edoxaban, and dabigatran etexilate. Remedial dosing regimens based on population pharmacokinetic (PK)-pharmacodynamic (PD) modeling and simulation strategies were developed to expeditiously restore drug concentration or PD biomarkers within the therapeutic range. Population PK-PD characteristics of DOACs were retrieved from previously published literature. The effects of factors that influence PK and PD parameters were assessed for their impact on remedial dosing regimens. A web-based dashboard was established with R-shiny to recommend remedial dosing regimens based on patient traits, dosing schedules, and delay duration. Addressing delayed or missed doses relies on the delay time and specific DOACs involved. Additionally, age, body weight, renal function, and polypharmacy may marginally affect remedial strategies. The proposed remedial dosing strategies surpass current recommendations, with less deviation time beyond the therapeutic range. The online dashboard offers quick and convenient solutions for addressing missed or delayed DOACs, enabling individualized remedial dosing strategies based on patient characteristics to mitigate the risks of bleeding and thrombosis.

摘要

不遵医嘱服用直接口服抗凝药物(DOAC)可能会增加血栓栓塞或出血的风险,而延迟或漏服是最常见的不遵医嘱类型。目前监管机构或指南针对这一问题的建议缺乏证据,也没有考虑到个体差异。本研究旨在开发 DOAC(包括利伐沙班、阿哌沙班、依度沙班和达比加群酯)延迟或漏服时的个体化补救剂量策略。基于群体药代动力学(PK)-药效学(PD)建模和模拟策略开发了补救剂量方案,以迅速将药物浓度或 PD 生物标志物恢复到治疗范围内。从先前发表的文献中检索了 DOAC 的 PK-PD 特征。评估了影响 PK 和 PD 参数的因素对补救剂量方案的影响。使用 R-shiny 建立了一个基于网络的仪表板,根据患者特征、给药方案和延迟时间来推荐补救剂量方案。解决延迟或漏服问题取决于延迟时间和具体的 DOAC。此外,年龄、体重、肾功能和多药治疗可能会对补救策略产生轻微影响。与目前的建议相比,所提出的补救剂量策略具有更小的偏差时间,超出治疗范围。在线仪表板提供了一种快速便捷的解决方案,用于解决漏服或延迟的 DOAC,能够根据患者特征制定个体化的补救剂量策略,从而降低出血和血栓形成的风险。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad0b/11612359/4aefa704f53a/BLOODA_ADV-2024-013854-ga1.jpg

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