Simultaneous Determination of Multiple Anti‐Seizure Medications in Human Plasma Using High‐Performance Liquid Chromatography‐Tandem Mass Spectrometry with Positive/Negative Ion‐Switching Ionization Mode for Therapeutic Drug Monitoring

ABSTRACT Monotherapy or combination therapy with anti‐seizure medications (ASMs) remains the cornerstone of epilepsy treatment. Therapeutic drug monitoring is important for individualized ASM treatment and for optimizing outcomes in patients with epilepsy. Therefore, the simultaneous and accurate quantification of ASMs is necessary and helpful for clinical use. In this study, a new method was developed to simultaneously quantify carbamazepine, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, sodium valproate, topiramate, and an active metabolite of oxcarbazepine, 10, 11‐dihydro‐10‐hydroxycarbamazepine, in human plasma by high‐performance liquid chromatography‐tandem mass spectrometry using the positive/negative ion‐switching ionization mode. The method was assessed for accuracy, precision, linearity, recovery, and matrix effects according to the criteria of the U.S. Food and Drug Administration Bioanalytical Method Validation Guidelines for Industry for Bioanalytical Methods. The lower limit of quantification was determined to be 0.001–25 µg/mL for each analyte. The intra‐ and inter‐day precision values had <14.6% coefficients of variation, and the accuracy ranged from 85.3% to 113% at the three levels of quality control. In addition, this method was successfully applied to therapeutic drug monitoring of ASMs in patients with epilepsy. This method allows for simple preparation, accurate quantification, and the determination of different ASMs without requiring analytical method switching, making it particularly suitable for therapeutic drug monitoring in busy clinical and hospital laboratory settings.