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 C column. All antiepileptic drugs were separated and quantified in 6 min, without interference. A good linearity was observed all over the calibration range (r > 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.

Development and Validation of a HPTLC Method to Determine Serum Zonisamide levels for Therapeutic Drug Monitoring in Clinical Settings

“…When the results of the developed and validated method were compared to those obtained using high performance liquid chromatography (HPLC), HPTLC and gas chromatography, there were no significant difference in the accuracy and precision, the only limitation was that the LOQ and LOD were higher in the present study as compared to those obtained using the HPLC method. The lowest LOQ in HPLC documented in literature was approximately 0.1 µg/ml [18,19] while in the present study, it was 3.15 µg/ml. However, the LOQ of this HPTLC method is well below the therapeutic range, which is 10 to 40 µg/ml and therefore, could be used reliably to carry out therapeutic drug monitoring.…”

Simultaneous UPLC‐MS/MS determination of antiepileptic agents for dose adjustment

“…The first study was reported by Carlow, Shi, and Schofield (). The second study was reported by Julien Dupouey, Doudka, Belo, Blin, and Guilhaumou (). Both studies were efficient for the determination of the AED.…”

Simultaneous Determination of Phenobarbital, Phenytoin, Carbamazepine and Carbamazepine-10,11-epoxide in Plasma of Epileptic Patients

“…1,2 The pharmacotherapy with AEDs is the first choice for the treatment of epilepsy as it controls the occurrence of unpredictable epileptic seizures on approximately two thirds of the patients. 3 Approximately 30-40% of patients do not achieve seizure control with a single AED and rational polytherapy with the goal of finding combinations of AEDs that have favorable characteristics, has become of greater importance. 4 Before that one should ensure that the drug has reached its therapeutic range and there is no possibility to increase its daily dose.…”

“…Because of their narrow therapeutic range in adults (10-40 µg mL -1 , 5-20 µg mL -1 and 2-12 µg mL -1 , respectively for PB, PHT and CBZ) 5 and their complex pharmacokinetic properties, their blood levels should be monitored. Therapeutic ranges of PB, PHT and CBZ in children are 20-60 µg mL -1 , 3 6-11 µg mL -1 6 and 4-12 µg mL -1 , 7 respectively. Lethal concentrations of PB and PHT are 50 µg mL -1 for both drugs 5 and fatalities could be observed in CBZ serum concentrations of >20 µg mL -1 5 or >39 µg mL -1 .…”