Fixed dose daptomycin: An opportunity for pharmacokinetic/pharmacodynamic optimization in Staphylococcus aureus infections.

IF 2.9 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Pharmacotherapy Pub Date : 2024-08-01 Epub Date: 2024-07-30 DOI:10.1002/phar.4602
Katie B Olney, Manjunath P Pai, Jenni K Thomas, Donna R Burgess, William J Olney, Rebecca A Bruning, Kamron A Griffith, Danielle V Casaus, Elizabeth Crance, James Z Porterfield, David S Burgess
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引用次数: 0

Abstract

Background: Daptomycin is a high-use intravenous antimicrobial agent affording the convenience of once-daily dosing. Prior studies suggest an opportunity to use a more operationally convenient fixed rather than weight-based dosing but this approach has not been studied prospectively.

Methods: This study quantified the probability of toxicity and efficacy end points by prospectively testing a fixed dose regimen of daptomycin (750 mg) in obese and non-obese adults. At least, three daptomycin concentrations were measured at steady-state for each patient. A population pharmacokinetic model was constructed to evaluate concentration-time profiles and investigate covariates of daptomycin clearance. Simulations were performed to evaluate the probability of achieving efficacy (24-h area under the curve (AUC0-24) ≥ 666 mg∙h/L) and toxicity (minimum concentration (C min) ≥24.3 mg/L) targets for fixed (500-1000 mg) and weight-based (6-12 mg/kg) daptomycin doses.

Results: Thirty-one patients (16 females, 15 males) with median (interquartile range (IQR)) age of 50 (30, 62) years and weight of 74 (54, 156) kg were included in the final analysis. Fixed dose daptomycin (750 mg) resulted in similar exposure across weights with a median (IQR) AUC0-24 of 819 (499, 1501) mg∙h/L and 749 (606, 1265) mg∙h/L in patients weighing ≤74 kg and >74 kg, respectively. Overall, male sex and increased kidney function necessitate higher fixed and weight-based doses to achieve efficacy. Creatine phosphokinase elevation was observed in two patients (6.5%) and predicted to be lower with fixed versus weight-based regimens.

Conclusions: Fixed daptomycin dosing adjusted for sex and kidney function is expected to improve the efficacy-to-toxicity ratio, transitions of care, and costs compared to weight-based doses. However, no empiric dosing approach is predicted to achieve ≥90% efficacy while minimizing the risk of toxicity, so therapeutic drug monitoring should be considered on a patient-specific basis.

固定剂量达托霉素:在金黄色葡萄球菌感染中优化药代动力学/药效学的机会。
背景:达托霉素是一种使用率很高的静脉注射抗菌药物,每天给药一次非常方便。之前的研究表明,有机会使用操作更方便的固定剂量而非基于体重的剂量,但这种方法尚未进行过前瞻性研究:本研究通过对肥胖和非肥胖成人使用达托霉素(750 毫克)的固定剂量方案进行前瞻性试验,量化了毒性和疗效终点的概率。每名患者在稳态时至少测量三次达托霉素浓度。构建了一个群体药代动力学模型,以评估浓度-时间曲线并研究达托霉素清除率的协变量。模拟评估了固定剂量(500-1000 毫克)和基于体重(6-12 毫克/千克)的达托霉素达到疗效(24 小时曲线下面积 (AUC0-24) ≥ 666 毫克∙小时/升)和毒性(最低浓度 (Cmin) ≥24.3 毫克/升)目标的概率:31名患者(16名女性,15名男性)被纳入最终分析,他们的中位数(四分位数间距,IQR)年龄为50(30,62)岁,体重为74(54,156)公斤。固定剂量达托霉素(750毫克)在不同体重患者中的暴露量相似,中位数(IQR)AUC0-24分别为819(499,1501)毫克/小时/升和749(606,1265)毫克/小时/升,体重≤74公斤和大于74公斤的患者的AUC0-24分别为749(606,1265)毫克/小时/升和749(606,1265)毫克/小时/升。总体而言,男性和肾功能增强的患者需要使用更高的固定剂量和基于体重的剂量才能达到疗效。在两名患者(6.5%)中观察到肌酸磷酸激酶升高,预计固定剂量与按体重给药方案相比,肌酸磷酸激酶升高更低:结论:根据性别和肾功能调整达托霉素的固定剂量有望改善疗效-毒性比、护理转换和成本。然而,没有一种经验性给药方法能在最大程度降低毒性风险的同时达到≥90%的疗效,因此应根据患者的具体情况考虑进行治疗药物监测。
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来源期刊
Pharmacotherapy
Pharmacotherapy 医学-药学
CiteScore
7.80
自引率
2.40%
发文量
93
审稿时长
4-8 weeks
期刊介绍: Pharmacotherapy is devoted to publication of original research articles on all aspects of human pharmacology and review articles on drugs and drug therapy. The Editors and Editorial Board invite original research reports on pharmacokinetic, bioavailability, and drug interaction studies, clinical trials, investigations of specific pharmacological properties of drugs, and related topics.
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