Amikacin Dosing Adjustment in Critically Ill Oncologic Patients: A Study with Real-World Patients, PBPK Analysis, and Digital Twins.

IF 4.9 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Juliana Queiroz da Silva, Natália Valadares de Moraes, Rita Estrela, Diogenes Coelho, Diego Feriani, Karen Migotto, Pedro Caruso, Ivan Leonardo França E Silva, Daiane de Araujo Oliveira, João Paulo Telles, Fernanda de Lima Moreira
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引用次数: 0

Abstract

Background/Objectives: Guidelines recommend adjusting amikacin dosing based on patients' renal function. Nevertheless, for critically ill cancer patients, the renal function equations based on serum creatinine levels have low or no correlation with amikacin clearance. Considering this, using real-world data, we built an amikacin PBPK model to predict amikacin plasma concentrations in critically ill oncologic patients stratified by renal impairment levels. Further, the model was applied for dose stratification and individualization (digital twin strategy) in this population. Methods: In the Therapeutic Drug Monitoring (TDM) study, 368 amikacin pharmacokinetic analyses from 184 critically ill cancer patients were enrolled in three cohorts. A full-body PBPK model was developed using PK-Sim v. 11.3. Results: The final PBPK model accounted for two groups of critically ill cancer patients with mild (creatinine clearance; CLcr ≥ 60 mL/min) or severe (CLcr < 60 mL/min) renal dysfunction. In the dose stratification strategy, at the 7th dose, cancer patients with CLcr ≥ 60 mL/min under regimens 20 mg/kg (q24h); 25 mg/kg (q24h); 25 mg/kg (q48h); and 30 mg/kg (q72h) have probability of ≥69% of the patients achieving the efficacy target (AUC/MIC > 80, MIC of 4 mg/L), while cancer patients with CLcr < 60 mL/min under regimens 7.5 mg/kg (q24h); 15 mg/kg (q24h); 15 mg/kg (q48h); and 20 mg/kg (q36h) have ≥90% probability of achieving the same efficacy target. Conclusions: Our MIPD approach demonstrates potential in optimizing amikacin dosing for critically ill cancer patients. However, it does not eliminate the need for TDM due to unexplained variability still not accounted for by the PBPK model.

危重肿瘤患者阿米卡星剂量调整:现实世界患者、PBPK分析和数字双胞胎的研究。
背景/目的:指南建议根据患者的肾功能调整阿米卡星的剂量。然而,对于危重癌症患者,基于血清肌酐水平的肾功能方程与阿米卡星清除率相关性较低或无相关性。考虑到这一点,我们使用现实世界的数据,建立了一个阿米卡星PBPK模型来预测按肾损害程度分层的危重肿瘤患者阿米卡星血浆浓度。此外,该模型应用于该人群的剂量分层和个体化(数字双胞胎策略)。方法:在治疗药物监测(TDM)研究中,对184例危重癌症患者的368例阿米卡星药代动力学进行分析,分为三个队列。采用PK-Sim v. 11.3建立全身PBPK模型。结果:最终PBPK模型占两组危重癌症患者肌酸酐清除率轻度;CLcr≥60ml /min)或严重(CLcr < 60ml /min)肾功能不全。在剂量分层策略中,在第7次剂量时,CLcr≥60 mL/min的癌症患者在20mg /kg (q24h)方案下;25mg /kg (q24h);25mg /kg (q48h);和30 mg/kg (q72h)的患者达到疗效目标的概率≥69% (AUC/MIC为80,MIC为4 mg/L),而CLcr < 60 mL/min的癌症患者在7.5 mg/kg (q24h)的方案下;15mg /kg (q24h);15mg /kg (q48h);20 mg/kg (q36h)达到相同疗效目标的概率≥90%。结论:我们的MIPD方法显示了优化阿米卡星给药危重癌症患者的潜力。然而,这并不能消除对TDM的需求,因为PBPK模型仍然没有解释不明的变异性。
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来源期刊
Pharmaceutics
Pharmaceutics Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
7.90
自引率
11.10%
发文量
2379
审稿时长
16.41 days
期刊介绍: Pharmaceutics (ISSN 1999-4923) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers, communications,  and short notes. Covered topics include pharmacokinetics, toxicokinetics, pharmacodynamics, pharmacogenetics and pharmacogenomics, and pharmaceutical formulation. Our aim is to encourage scientists to publish their experimental and theoretical details in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.
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