Therapeutic drug monitoring of valproic acid using a dried plasma spot sampling device

Abstract

Valproic acid (VPA) dosing needs to be individualized for epilepsy patients through therapeutic drug monitoring (TDM). The patients must show up in the clinic at the therapeutic window time to venipuncture sample. Dried plasma spot (DPS) sampling is an alternative way to replace conventional venipuncture sampling. The aim of this study was to develop and validate a DPS-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to monitor VPA in a routine clinical laboratory setting. We compare the DPS with the wet plasma method of clinical samples by LC-MS/MS. The method was linear over the dynamic range of 10-200 μg/ml (covering entire therapeutic range) with a correlation coefficient r 2 ≥ 0.995. Both the DPS and wet plasma methods were fully validated for the accuracy, precision, recovery, and matrix effect. The analyte stability was examined under conditions mimicking the sample storage, transport, and analysis procedures. A clinical study with epilepsy patients receiving VPA (n = 35) showed that, after correction for hematocrit (HCT), plasma concentrations can be successfully calculated from the DPS quantification results. Passing-Bablok regression coefficients showed no proportional bias between estimated and measured plasma concentrations. Similar agreement was found by Bland-Altman plots. The dried sample could be mailed to the clinical lab to test by regular mail service. So DPS can be used for drug monitoring with selfsampling strategy at the patient's convenient time and place specially for ambulatory patients not attending a clinic. K E Y W O R D S dried plasma spot, LC-MS/MS, microsampling strategy, therapeutic drug monitoring, valproic acid 1 | INTRODUCTION Valproic acid (2-propylpentanoic acid, VPA; Figure 1), a branched short-chain fatty acid derivative has been commonly used for the treatment of primary generalized epilepsy, partial seizures, and myoclonic seizures. 1,2 Because epilepsy often coexists with psychiatric illness, VPA has been employed in the treatment of bipolar disorder

Switching Between LC-ESI-MS/MS and EMIT Methods for Routine TDM of Valproic Acid in Pediatric Patients With Epilepsy: What Clinicians and Researchers Need to Know

“…In the study, the parent and daughter ions of VPA and the IS were the same, indicating that no fragmentation was performed and the LC-ESI-MS/MS method was run as pseudo MRM method. As other literatures reported previously ( Jain et al, 2007 ; Matsuura et al, 2008 ; Soni et al, 2016 ; Linder et al, 2018 ; Li et al, 2021 ), VPA did not produce noticeable fragment ions during ionization. On this basis, it seems that the MS/MS method has the same theoretical selectivity and sensitivity of single-MS spectrometry.…”

“…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. Additionally, 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 ). Though VPA represents a useful therapeutic alternative in the treatment of epilepsy, it exhibits high inter-subject variability, remarkably when enzyme-inducing or enzyme-inhibiting drugs are co-administered ( Methaneethorn, 2018 ).…”

Microsampling Devices for Routine Therapeutic Drug Monitoring—Are We There Yet?

“…One such device, the Noviplex (Novilytic, W Lafayette, IN) plasma extraction card, has been used to measure valproic acid, with results compared with the traditional plasma measurement. 52 The device uses a membrane to filter red cells out of the sample and deposits a fixed volume (2.5 or 3.8 mL) of plasma onto a paper disc. In this study, the DPS sample was prepared by dropping approximately 40 mL of blood onto the test area.…”

Dried plasma spot–based liquid chromatography–tandem mass spectrometry for the quantification of methotrexate in human plasma and its application in therapeutic drug monitoring

“…Compared with DBS, a disadvantage of traditional TDM is that it requires a centrifugation step to separate the plasma. However, this situation is changing given the availability of a new commercially available DPS card was introduced as a sampling device that can automatically separate plasma from the blood [34–37], avoiding the influence of various inherent HCT levels on quantitative analysis and the problem of uneven blood distribution on the DBS cards. Consequently, DPS cards can minimize the required downstream validation steps in the bioanalytical assay.…”