镰状细胞病患者左旋谷氨酰胺暴露的群体药代动力学分析:剂量和食物影响评估

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Clinical Pharmacokinetics Pub Date : 2024-03-01 Epub Date: 2024-02-24 DOI:10.1007/s40262-024-01349-4
Alina Sadaf, Min Dong, Amanda Pfeiffer, Teresa Latham, Theodosia Kalfa, Alexander A Vinks, Russell E Ware, Charles T Quinn
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引用次数: 0

摘要

背景和目的:左旋谷氨酰胺是一种治疗儿童和成人镰状细胞病的药物。目前尚未对镰状细胞病患者的左旋谷氨酰胺药代动力学进行全面评估。我们的目的是评估与正常人相比,镰状细胞病患者长期用药、多剂量水平和食物摄入对左旋谷氨酰胺暴露的影响:我们对患有镰状细胞病的儿童和成人参与者(8 人)以及成人健康志愿者(4 人)进行了开放标签的左旋谷氨酰胺剂量递增试验,共提供了 400 个血浆左旋谷氨酰胺浓度。每位参与者在 3 周内接受三次剂量递增的口服治疗(每次 0.1 和 0.3 克/千克,每天两次;每次 0.6 克/千克,每天一次)。使用离子交换色谱法对血浆中的左旋谷氨酰胺浓度进行量化。进行了非室药代动力学分析和群体药代动力学分析:结果:L-谷氨酰胺的吸收和消除速度很快,在整个研究过程中,L-谷氨酰胺的基线(给药前)浓度没有显著变化,表明没有药物蓄积。药代动力学用一室模型和一阶动力学进行了最佳描述。剂量归一化峰值浓度随着剂量的增加而降低,这表明口服左旋谷氨酰胺的药代动力学是受容量限制的非线性。协变量分析表明,L-谷氨酰胺的基线浓度与谷氨酰胺清除率呈负相关,而剂量与分布容积呈正相关。食物摄入量对谷氨酰胺清除率没有明显影响,这表明L-谷氨酰胺可以在进食或不进食的情况下服用:我们报告了第一例多剂量、长期口服左旋谷氨酰胺治疗的药代动力学研究,以及第一例镰状细胞病人群左旋谷氨酰胺药代动力学分析。这些研究结果可以优化镰状细胞病患者的左旋谷氨酰胺剂量,从而最大限度地提高治疗效果:该试验已在ClinicalTrials.gov(NCT04684381)上注册。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A Population Pharmacokinetic Analysis of L-Glutamine Exposure in Patients with Sickle Cell Disease: Evaluation of Dose and Food Effects.

A Population Pharmacokinetic Analysis of L-Glutamine Exposure in Patients with Sickle Cell Disease: Evaluation of Dose and Food Effects.

Background and objective: L-Glutamine is a treatment for children and adults with sickle cell disease. A comprehensive evaluation of the pharmacokinetics of L-glutamine in sickle cell disease has not been conducted. We aimed to assess the effects of long-term dosing, multiple dose levels, and food intake on L-glutamine exposure in patients with sickle cell disease compared to normal participants.

Methods: We conducted an open-label dose-ascending trial of L-glutamine in pediatric and adult participants with sickle cell disease (N = 8) and adult healthy volunteers (N = 4), providing a total of 400 plasma L-glutamine concentrations. Each participant received three ascending oral doses (0.1 and 0.3 g/kg twice daily and 0.6 g/kg once daily) over 3 weeks. Plasma L-glutamine concentrations were quantified using ion exchange chromatography. Both a non-compartmental pharmacokinetic analysis and a population pharmacokinetic analysis were performed.

Results: L-glutamine had rapid absorption and elimination, and there was no significant change in the baseline (pre-dose) L-glutamine concentration throughout the study, indicating no drug accumulation. Pharmacokinetics was best described by a one-compartment model with first-order kinetics. The dose-normalized peak concentration decreased with dose escalation, indicating the capacity-limited non-linear pharmacokinetics of oral L-glutamine. A covariate analysis showed that baseline L-glutamine concentrations correlated negatively with glutamine clearance, whereas dose positively correlated with volume of distribution. Food intake did not significantly affect glutamine clearance, indicating that L-glutamine can be taken with or without food.

Conclusions: We report the first pharmacokinetic study of multiple-dose, long-term oral L-glutamine therapy and the first population pharmacokinetic analysis of L-glutamine for sickle cell disease. These findings may permit optimized dosing of L-glutamine for patients with sickle cell disease to maximize treatment benefits.

Clinical trial registration: This trial is registered at ClinicalTrials.gov (NCT04684381).

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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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