Abstract
Background: Valproic acid (VPA) is a widely used antiseizure medication and its dosing needs to be tailored individually through therapeutic drug monitoring (TDM) to avoid or prevent toxicity. Currently, immune-enzymatic assays such as Enzyme Multiplied Immunoassay Technique (EMIT), and Liquid Chromatography (LC)-based techniques, particularly coupled to Electrospray Ionization Tandem Mass Spectrometry (LC–ESI-MS/MS), resulting a potential lack of concordance between laboratories. Methods: In this study, plasma VPA concentrations were determined for 711 pediatric patients with epilepsy by a routine EMIT assay and by a validated in-house LC-ESI-MS/MS method on the same group of samples, aimed to address the aforementioned concern. Consistency between two assays was evaluated using linear regression and Bland-Altman analysis. Results: The calibration curve was linear in the range of 5.00–300 μg/ml for LC-ESI-MS/MS method and 1.00–150 μg/ml for EMIT assay, respectively. The two methods were proven to be accurate with quality control samples. As a result, a significant correlation between two methods was obtained with a regression equation described as (r 2 = 0.9281). Bland-Altman plot showed a mean bias of 14.5 μg/ml (95% confidence interval (CI) (−0.2, 29.2) and a mean increase of 27.8% (95% CI (3.3, 52.4) measured by EMIT assay more than that measured by LC-ESI-MS/MS method. Conclusion: In conclusion, two methods were closely correlated, but EMIT assay overestimate VPA levels in human plasma compared with LC-ESI-MS/MS method. Due to the observed significant discordance between the tested methods, switching from immunoassays to LC-based techniques for TDM of VPA deserves close attention and therapeutic range of 35.0–75.0 μg/ml may be feasible. However, further studies are needed to evaluate the eligibility of this alternative range in the clinical practice. Clinicians should be informed when switching the VPA quantitation methods during the clinical practice.
Highlights
Valproic acid (2-propyl-pentanoic acid, VPA), commercially available in most countries during the 1970s, is one of the first-line option for the treatment of epilepsy, especially prescribed in pediatric epilepsy because of its various mechanisms of action and acceptable safety profiles
The aims of this study were: 1) to develop and validate an Liquid Chromatography (LC)-ESI-MS/MS method for the analysis of VPA; 2) to evaluate the correlation between Enzyme Multiplied Immunoassay Technique (EMIT) and LC-ESI-MS/MS methods in VPA determination using samples from pediatric patients with epilepsy; and 3) to discuss the method switching from EMIT to LC-ESI-MS/MS for routine therapeutic drug monitoring (TDM) of VPA in clinical laboratories
The blank human plasma from six different sources was tested for selectivity and the results proved that no endogenous substances interfered with VPA and Internal standard (IS)
Summary
Valproic acid (2-propyl-pentanoic acid, VPA), commercially available in most countries during the 1970s, is one of the first-line option for the treatment of epilepsy, especially prescribed in pediatric epilepsy because of its various mechanisms of action and acceptable safety profiles. It is being used with increasing frequency for the management of a range of psychiatric conditions (Fleming and Chetty, 2006; Zighetti et al, 2015; Li et al, 2021). Valproic acid (VPA) is a widely used antiseizure medication and its dosing needs to be tailored individually through therapeutic drug monitoring (TDM) to avoid or prevent toxicity. Immune-enzymatic assays such as Enzyme Multiplied Immunoassay Technique (EMIT), and Liquid Chromatography (LC)-based techniques, coupled to Electrospray Ionization Tandem Mass Spectrometry (LC–ESI-MS/ MS), resulting a potential lack of concordance between laboratories
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