Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA.
Department of Emergency Medicine, University of Minnesota, Minneapolis, Minnesota, USA.
Pharmacotherapy. 2023 Dec;43(12):1240-1250. doi: 10.1002/phar.2882. Epub 2023 Oct 11.
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.
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.
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 were adaptively randomized to receive intravenous L-carnitine (6 grams, 12 grams, or 18 grams) or placebo.
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.
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.
左卡尼汀（L-肉碱）作为一种代谢治疗药物，在败血症性休克中显示出一定的前景，其死亡率接近 40%。然而，高剂量（≥6 克）静脉补充会导致广泛的血清浓度范围。我们旨在描述高剂量左卡尼汀的群体药代动力学（PK），测试各种肾功能估计值，并评估 PK 参数与败血症性休克患者治疗前代谢物的相关性，以描述药物反应。
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。测试了各种肾功能估计值、患者人口统计学特征、剂量、器官功能障碍等作为群体协变量。
我们利用了 L-肉碱在依赖升压药物的败血症性休克的 II 期试验中的血清样本和代谢组学数据。在治疗开始时（T0）；输注结束时（T12）；以及治疗开始后 24、48 和 72 小时采集血清。
患者适应性随机接受静脉内左卡尼汀（6 克、12 克或 18 克）或安慰剂治疗。
最终数据集包括 130 名随机接受左卡尼汀的患者的 542 份血清样本。一个具有线性消除和固定分布容积（17.1 升）的两室模型最能描述数据，并作为基础结构模型。以消除速率常数（k）的肾功能估计值作为协变量，可可靠地改善模型拟合度。基于 2021 年慢性肾脏病流行病学合作（CKD-EPI）方程与肌酐和胱抑素 C 的估计肾小球滤过率（eGFR），优于肌酐清除率（Cockcroft-Gault）和使用自我识别种族调整的旧版 CKD-EPI 方程。
败血症性休克患者的高剂量左卡尼汀补充剂由一个两室群体 PK 模型很好地描述。利用胱抑素 C 的肾功能估计值提供了更好的模型拟合度。未来对高剂量左卡尼汀补充剂的研究应考虑基于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方案。
