Therapeutic Drug Monitoring of 6 New-Generation Antiseizure Medications Using a Mass Spectrometry Method: Analysis of 2-Year Experience in a Large Cohort of Korean Epilepsy Patients

Epilepsy affects 45.9 million people (including both idiopathic and secondary epilepsy) worldwide, accounting for 0.6% of the overall population.1 Epilepsy remains an important cause of mortality and disability, with mortality [...]
* Context.--New-generation antiseizure medications (ASMs) are increasingly prescribed, and therapeutic drug monitoring (TDM) has been proposed to improve clinical outcome. However, clinical TDM data on new-generation ASMs are scarce. Objective.--To develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for therapeutic drug monitoring (TDM) of 6 new-generation ASMs in serum and analyze the clinical TDM data from a large cohort of Korean patients with epilepsy. Design.--Stable isotope-labeled internal standards were added to protein precipitations of serum. One microliter of sample was separated on an Agilent Poroshell EC-C18 column, and lacosamide, perampanel, gabapentin, pregabalin, vigabatrin, and rufinamide were simultaneously quantified by Agilent 6460 triple-quad mass spectrometer in multiple-reaction monitoring mode. Linearity, sensitivity, precision, accuracy, specificity, carryover, extraction recovery, and matrix effect were evaluated. TDM data of 458 samples from 363 Korean epilepsy patients were analyzed. Results.--The method was linear with limit of detection less than 0.05 ig/mL in all analytes. Intraassay and interassay imprecisions were less than 5% coefficient of variation. Accuracy was within [+ or -] 15% bias. Extraction recovery ranged from 85.9% to 98.8%. A total of 88% (403 of 458) were on polypharmacy, with 29% (118 of 403) using concomitant enzyme inducers. Only 38% (175 of 458) of the concentrations were therapeutic, with 53% (244 of 458) being subtherapeutic. Drug concentration and concentration-to-dose ratio were highly variable among individuals for all 6 ASMs. Conclusions.--A simple and rapid LC-MS/MS method for TDM of 6 ASMs was developed and successfully applied to clinical practice. These large-scale TDM data could help establish an effective monitoring strategy for these drugs. (Arch Pathol Lab Med. 2025;149:67-74; doi: 10.5858/arpa.2023-0386-OA)