Background

Current guidelines recommend therapeutic drug monitoring as a critical component of valproic acid (VPA) therapy. Due to high protein binding, the active unbound (free) portion of VPA can be misrepresented by total VPA serum levels in certain clinical scenarios. Monitoring free VPA serum levels may be warranted when assessing the clinical response to VPA therapy.

Objectives

The aims were to conduct a systematic review to identify a therapeutic range for free VPA serum levels; to explore the correlation of free VPA serum levels with clinical toxicity and therapeutic benefit; and to examine predictors of discordance between free and total VPA levels.

Methods

Medline, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, BIOSIS Previews, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from the time of database inception to June 20, 2021. Randomized controlled trials and observational studies that evaluated any patient receiving VPA with free VPA level monitoring were included.

Results

Of 189 citations, we identified 27 relevant studies, which included 14 observational studies, two case series, and 11 case reports. Three studies provided a therapeutic range for free VPA levels between 20 and 410 μmol/L. Two studies suggested the occurrence of hyperammonemia and thrombocytopenia at free VPA serum levels above 60 µmol/L and 103.3 µmol/L, respectively. Two studies suggested an upper limit for neurotoxicity at free VPA serum levels of 70 µmol/L and 207.9 µmol/L. Hypoalbuminemia was identified as a predictor of therapeutic discordance.

Conclusions

This review demonstrates a paucity of data informing the clinical utility of free VPA serum levels. Further high-quality trials are needed to validate an optimal therapeutic range for free VPA levels.

中文翻译：

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游离丙戊酸水平的临床药代动力学监测：系统评价

背景

目前的指南建议将治疗药物监测作为丙戊酸 (VPA) 治疗的重要组成部分。由于高蛋白结合，在某些临床情况下，VPA 的活性未结合（游离）部分可能会被总 VPA 血清水平所误报。在评估对 VPA 治疗的临床反应时，可能需要监测游离 VPA 血清水平。

目标

目的是进行系统评价以确定游离 VPA 血清水平的治疗范围；探讨游离 VPA 血清水平与临床毒性和治疗益处的相关性；并检查游离 VPA 水平和总 VPA 水平之间不一致的预测因子。

方法

从数据库开始到 2021 年 6 月 20 日，搜索了 Medline、EMBASE、Cochrane 对照试验中央登记册 (CENTRAL)、PsycINFO、BIOSIS 预览和护理和相关健康文献累积索引 (CINAHL)。随机对照试验和观察包括评估任何接受 VPA 且免费监测 VPA 水平的患者的研究。

结果

在 189 篇引用中，我们确定了 27 篇相关研究，其中包括 14 篇观察性研究、两个病例系列和 11 篇病例报告。三项研究提供了 20 至 410 μmol/L 之间游离 VPA 水平的治疗范围。两项研究表明，游离 VPA 血清水平分别高于 60 µmol/L 和 103.3 µmol/L 时会发生高氨血症和血小板减少症。两项研究表明游离 VPA 血清水平的神经毒性上限为 70 µmol/L 和 207.9 µmol/L。低白蛋白血症被确定为治疗不一致的预测因子。

结论

这篇综述表明缺乏有关游离 VPA 血清水平临床效用的数据。需要进一步的高质量试验来验证游离 VPA 水平的最佳治疗范围。