Development and Validation of a UHPLC-MS/MS-Based Method to Quantify Cenobamate in Human Plasma Samples

Area of Science:

• Pharmacology
• Analytical Chemistry
• Clinical Pharmacology

Background:

• Cenobamate (CNB) is a novel antiseizure medication (ASM) approved for uncontrolled partial-onset seizures in adults.
• Its exact mechanism of action is not fully elucidated, but it involves voltage-gated sodium channels and GABA ion channels.
• CNB exhibits significant oral bioavailability and interacts with co-administered ASMs and CYP450 substrates, necessitating therapeutic drug monitoring.

Purpose of the Study:

• To develop and validate a sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for quantifying cenobamate (CNB) in human plasma.
• To apply the validated method for evaluating the pharmacokinetic profile of CNB in non-adult patients.
• To assess the relationship between CNB dosage, plasma concentrations, and seizure control.

Main Methods:

• Development and validation of a UHPLC-MS/MS analytical method for CNB quantification in human plasma, adhering to current guidelines.
• Preliminary application of the method to monitor plasma CNB concentrations in two non-adult patients over a two-month period.
• Pharmacokinetic parameter evaluation based on serial plasma sampling.

Main Results:

• A validated UHPLC-MS/MS method was successfully established for accurate CNB measurement in plasma.
• Preliminary pharmacokinetic data from two non-adult patients demonstrated a linear increase in plasma CNB concentrations with escalating dosage.
• Both patients achieved a seizure-free state when maintained at a daily dose of 150 mg.

Conclusions:

• The developed UHPLC-MS/MS method provides a reliable tool for therapeutic drug monitoring of cenobamate.
• This study presents the first pharmacokinetic evaluation of CNB in non-adult patients, showing dose-proportional increases in plasma levels.
• Achieving a seizure-free state at 150 mg/day highlights the potential efficacy of CNB in this population, warranting further investigation.