肾功能是败血症休克大剂量左旋肉碱药代动力学反应的关键驱动因素。

IF 2.9 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pharmacotherapy Pub Date : 2023-12-01 Epub Date: 2023-10-11 DOI:10.1002/phar.2882
Theodore S Jennaro, Michael A Puskarich, Thomas L Flott, Laura A McLellan, Alan E Jones, Manjunath P Pai, Kathleen A Stringer
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引用次数: 0

摘要

背景:左旋卡尼汀(L-肉碱)已显示出作为感染性休克的代谢疗法的前景,感染性休克死亡率接近40%。但是,高剂量(≥ 6克)静脉内补充导致广泛的血清浓度范围。目的:我们试图描述高剂量L-肉碱的群体药代动力学(PK),测试对肾功能的各种估计,并评估PK参数与治疗前代谢产物的相关性,以描述感染性休克患者的药物反应。方法:我们利用了L-肉碱治疗血管升压药依赖性感染性休克的II期试验的血清样本和代谢组学数据。患者自适应地随机接受静脉注射L-肉碱(6克、12克或18克)或安慰剂。在基线(T0)采集血清;输液结束(T12);以及治疗开始后24、48和72小时。使用建模平台Monolix中的非线性混合效应模型对基线归一化浓度进行群体PK分析。对肾功能、患者人口统计学、接受的剂量和器官功能障碍的各种估计值作为群体协变量进行了测试。结果:最终数据集包括来自130名随机接受左旋肉碱治疗的患者的542份血清样本。具有线性消除和固定分配体积(17.1升)的两室模型最好地描述了数据,并作为基础结构模型。肾功能估计作为消除率常数(k)的协变量可靠地改进了模型拟合。基于2021年慢性肾脏病流行病学合作(CKD-EPI)方程和肌酸酐和胱抑素C的估计肾小球滤过率(eGFR)优于肌酸酐清除率(Cockcroft-Gault)和使用自我识别种族调整的旧CKD-EPI方程。结论:在感染性休克患者中,高剂量L-肉碱的补充通过两室群体PK模型得到了很好的描述。肾功能评估表明,利用胱抑素C提供了优越的模型拟合度。未来对高剂量L-肉碱补充的研究应考虑基线代谢状态和基于肾功能的剂量调整,而不是固定或基于体重的给药模式。
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Kidney function as a key driver of the pharmacokinetic response to high-dose L-carnitine in septic shock.

Study objective: Levocarnitine (L-carnitine) has shown promise as a metabolic-therapeutic for septic shock, where mortality approaches 40%. However, high-dose (≥ 6 grams) intravenous supplementation results in a broad range of serum concentrations. We sought to describe the population pharmacokinetics (PK) of high-dose L-carnitine, test various estimates of kidney function, and assess the correlation of PK parameters with pre-treatment metabolites in describing drug response for patients with septic shock.

Design: Population PK analysis was done with baseline normalized concentrations using nonlinear mixed effect models in the modeling platform Monolix. Various estimates of kidney function, patient demographics, dose received, and organ dysfunction were tested as population covariates.

Data source: We leveraged serum samples and metabolomics data from a phase II trial of L-carnitine in vasopressor-dependent septic shock. Serum was collected at baseline (T0); end-of-infusion (T12); and 24, 48, and 72 h after treatment initiation.

Patients and intervention: Patients were adaptively randomized to receive intravenous L-carnitine (6 grams, 12 grams, or 18 grams) or placebo.

Measurements and main results: The final dataset included 542 serum samples from 130 patients randomized to L-carnitine. A two-compartment model with linear elimination and a fixed volume of distribution (17.1 liters) best described the data and served as a base structural model. Kidney function estimates as a covariate on the elimination rate constant (k) reliably improved model fit. Estimated glomerular filtration rate (eGFR), based on the 2021 Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation with creatinine and cystatin C, outperformed creatinine clearance (Cockcroft-Gault) and older CKD-EPI equations that use an adjustment for self-identified race.

Conclusions: High-dose L-carnitine supplementation is well-described by a two-compartment population PK model in patients with septic shock. Kidney function estimates that leverage cystatin C provided superior model fit. Future investigations into high-dose L-carnitine supplementation should consider baseline metabolic status and dose adjustments based on renal function over a fixed or weight-based dosing paradigm.

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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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