目前的头孢曲松剂量推荐方案适用于大多数危重症儿童：一项群体药代动力学建模和模拟研究的结果。

Current Ceftriaxone Dose Recommendations are Adequate for Most Critically Ill Children: Results of a Population Pharmacokinetic Modeling and Simulation Study.

机构信息

Department of Pharmacology and Toxicology, Radboud Institute of Health Sciences, Radboudumc, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands.

Division of Systems Biomedicine and Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.

出版信息

Clin Pharmacokinet. 2021 Oct;60(10):1361-1372. doi: 10.1007/s40262-021-01035-9. Epub 2021 May 26.

DOI:10.1007/s40262-021-01035-9

PMID:34036552

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8505376/

Abstract

BACKGROUND AND OBJECTIVE

Ceftriaxone is a cornerstone antibiotic for critically ill children with severe infections. Despite its widespread use, information on the pharmacokinetics of ceftriaxone is lacking in this population. We aimed to determine ceftriaxone pharmacokinetics in critically ill children and to propose ceftriaxone dosing guidelines resulting in adequate target attainment using population pharmacokinetic modeling and simulation.

METHODS

Critically ill children (aged 0-18 years) treated with intravenous ceftriaxone (100 mg/kg once daily, infused in 30 minutes) and a central or arterial line in place were eligible. Opportunistic blood sampling for total and unbound ceftriaxone concentrations was used. Population pharmacokinetic analysis was performed using non-linear mixed-effects modeling on NONMEM™ Version 7.4.3. Simulations were performed to select optimal doses using probability of target attainment for two pharmacokinetic targets of the minimum inhibitory concentration (MIC) reflecting the susceptibility of pathogens (f T > MIC 100% and fT > 4 × MIC 100%).

RESULTS

Two hundred and five samples for total and 43 time-matched samples for unbound plasma ceftriaxone concentrations were collected from 45 patients, median age 2.5 (range 0.1-16.7) years. A two-compartment model with bodyweight as the co-variate for volume of distribution and clearance, and creatinine-based estimated glomerular filtration rate as an additional covariate for clearance, best described ceftriaxone pharmacokinetics. For a typical patient (2.5 years, 14 kg) with an estimated glomerular filtration rate of 80 mL/min/1.73 m, the current 100-mg/kg once-daily dose results in a probability of target attainment of 96.8% and 60.8% for a MIC of 0.5 mg/L and 4 × MIC (2 mg/L), respectively, when using fT > MIC 100% as a target. For a 50-mg/kg twice-daily regimen, the probability of target attainment was 99.9% and 93.4%, respectively.

CONCLUSIONS

The current dosing regimen of ceftriaxone provides adequate exposure for susceptible pathogens in most critically ill children. In patients with an estimated glomerular filtration rate of > 80 mL/min/1.73 m or in areas with a high prevalence of less-susceptible pathogens (MIC ≥ 0.5 mg/L), a twice-daily dosing regimen of 50 mg/kg can be considered to improve target attainment.

CLINICAL TRIAL REGISTRATION

POPSICLE study (ClinicalTrials.gov, NCT03248349, registered 14 August, 2017), PERFORM study (ClinicalTrials.gov, NCT03502993, registered 19 April, 2018).

摘要

背景和目的

头孢曲松是治疗重症感染患儿的基石抗生素。尽管广泛应用，但该人群的头孢曲松药代动力学信息仍然缺乏。我们旨在通过群体药代动力学建模和模拟来确定重症患儿的头孢曲松药代动力学，并提出能够实现目标的头孢曲松剂量指南。

方法

纳入接受静脉注射头孢曲松（100mg/kg，每日 1 次，30 分钟输注）且有中心或动脉置管的 0-18 岁重症患儿。使用机会性血样采集总头孢曲松和游离头孢曲松浓度。使用 NONMEMTM Version 7.4.3 进行非线性混合效应建模进行群体药代动力学分析。通过概率目标达成度来选择最佳剂量，概率目标达成度用于反映病原体敏感性的最小抑菌浓度（MIC）的两个药代动力学目标（fT > MIC 100%和 fT > 4×MIC 100%）。

结果

45 例患儿共采集 205 份总头孢曲松和 43 份与时间匹配的游离血浆头孢曲松浓度样本，患儿中位年龄 2.5 岁（范围 0.1-16.7 岁）。体重作为分布容积和清除率的协变量，肌酐估算肾小球滤过率作为清除率的附加协变量的两室模型，能最好地描述头孢曲松的药代动力学。对于肾小球滤过率估计值为 80mL/min/1.73m2 的典型患儿（2.5 岁，14kg），当前 100mg/kg，每日 1 次剂量方案，当使用 fT > MIC 100%作为目标时，MIC 为 0.5mg/L 和 4×MIC（2mg/L）的目标达成概率分别为 96.8%和 60.8%。对于 50mg/kg，每日 2 次方案，目标达成概率分别为 99.9%和 93.4%。