title: Simultaneous determination of four antiepileptic drugs in human plasma samples using an ultra-high-performance liquid chromatography tandem mass spectrometry method and its application in therapeutic drug monitoring.
abstract: Therapeutic drug monitoring of antiepileptic drugs is widely practiced to achieve optimal efficacy and avoid adverse side effects. We describe an ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC/MS/MS) method developed for the monitoring of four frequently prescribed antiepileptic drugs - lamotrigine, levetiracetam, oxcarbazepine and topiramate. The main pharmacologically active metabolite of oxcarbazepine (mono-hydroxy-derivative metabolite, MHD) was also quantified. After addition of internal standards and a simple stage of protein precipitation, plasmatic samples were analyzed on a C18column. All antiepileptic drugs were separated and quantified in 6 min, without interference. A good linearity was observed all over the calibration range (r2> 0.99), up to 20 μg/mL (40 μg/mL for MHD). The limit of quantification was 0.20 μg/mL (0.40 μg/mL for MHD) with precision and accuracy ranging from 1.0 to 2.1% and from 96.7 to 110.8%, respectively. Intra- and inter-day precision and accuracy values were within 15%. No significant matrix effect was observed for all analytes. Clinical application was successfully evaluated in 259 samples from patients treated for epilepsy or bipolar disorders. In conclusion, a rapid, specific and sensitive UHPLC/MS/MS method was developed and validated for simultaneous quantification of antiepileptic drugs, suitable for therapeutic drug monitoring in neurology and psychiatry.
authors.affiliation: Service de Pharmacologie clinique et Pharmacovigilance, Hôpital de la Timone, 264 rue Saint Pierre, 13385, Marseille Cedex 5, France.|Pharmacologie intégrée et Interface clinique et industriel, Institut des Neurosciences Timone - CNRS 7289, Aix Marseille Université, Marseille, 13385, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Dupouey
authors.affiliation: Service de Pharmacologie clinique et Pharmacovigilance, Hôpital de la Timone, 264 rue Saint Pierre, 13385, Marseille Cedex 5, France.
authors.forename: Natalia
authors.initials: N
authors.lastname: Doudka
authors.affiliation: Service de Pharmacologie clinique et Pharmacovigilance, Hôpital de la Timone, 264 rue Saint Pierre, 13385, Marseille Cedex 5, France.
authors.forename: Séphora
authors.initials: S
authors.lastname: Belo
authors.affiliation: Service de Pharmacologie clinique et Pharmacovigilance, Hôpital de la Timone, 264 rue Saint Pierre, 13385, Marseille Cedex 5, France.|Pharmacologie intégrée et Interface clinique et industriel, Institut des Neurosciences Timone - CNRS 7289, Aix Marseille Université, Marseille, 13385, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Blin
authors.affiliation: Service de Pharmacologie clinique et Pharmacovigilance, Hôpital de la Timone, 264 rue Saint Pierre, 13385, Marseille Cedex 5, France.|Pharmacologie intégrée et Interface clinique et industriel, Institut des Neurosciences Timone - CNRS 7289, Aix Marseille Université, Marseille, 13385, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Guilhaumou
mesh_terms: D000927:Anticonvulsants / Q000097:blood*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D016903:Drug Monitoring; D006801:Humans; D057230:Limit of Detection; D012015:Reference Standards; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D000927:Anticonvulsants
keywords: LC-MS/MS; antiepileptic drugs; bipolar disorders; epilepsy; therapeutic drug monitoring