Interlaboratory Variability in the Quantification of New Generation Antiepileptic Drugs Based on External Quality Assessment Data

Abstract

Summary:Purpose: To assess interlaboratory variability in the determination of serum levels of new antiepileptic drugs (AEDs).Methods: Lyophilised serum samples containing clinically relevant concentrations of felbamate (FBM), gabapentin (GBP), lamotrigine (LTG), the monohydroxy derivative of oxcarbazepine (OCBZ; MHD), tiagabine (TGB), topiramate (TPM), and vigabatrin (VGB) were distributed monthly among 70 laboratories participating in the international Heathcontrol External Quality Assessment Scheme (EQAS). Assay results returned over a 15-month period were evaluated for precision and accuracy.Results: The most frequently measured compound was LTG (65), followed by MHD (39), GBP (19), TPM (18), VGB (15), FBM (16), and TGB (8). High-performance liquid chromatography was the most commonly used assay technique for all drugs except for TPM, for which two thirds of laboratories used a commercial immunoassay. For all assay methods combined, precision was <11% for MHD, FBM, TPM, and LTG, close to 15% for GBP and VGB, and as high as 54% for TGB (p < 0.001). Mean accuracy values were <10% for all drugs other than TGB, for which measured values were on average 13.9% higher than spiked values, with a high variability around the mean (45%). No differences in precision and accuracy were found between methods, except for TPM, for which gas chromatography showed poorer accuracy compared with immunoassay and gas chromatography-mass spectrometry.Conclusions: With the notable exception of TGB, interlaboratory variability in the determination of new AEDs was comparable to that reported with older-generation agents. Poor assay performance is related more to individual operators than to the intrinsic characteristics of the method applied. Participation in an EQAS scheme is recommended to ensure adequate control of assay variability in therapeutic drug monitoring.

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

“…A broad reference range of 20–200 ng/mL has been proposed [50]. Analytical issues have been a challenging problem in measurement of tiagabine serum/plasma concentrations, with some assays not achieving a low enough limit of sensitivity to measure the full range of clinically relevant free drug concentrations [160]. Multiple analytical methodologies have been reported for the measurement of tiagabine in plasma/serum including GC/MS [161] and HPLC [162].…”

Modern Methods for Analysis of Antiepileptic Drugs in the Biological Fluids for Pharmacokinetics, Bioequivalence and Therapeutic Drug Monitoring

“…The role of the TDM for TGB has not yet established. Nevertheless, its use in ascertaining compliance and manging patients that are overdosed would be helpful, provided that utmost care is dependent on ensuring the reliability of the analytical assay [206,207]. If morning were to be undertaken, sampling time in relation to dose is critical because large interdose fluctuation in concentrations occur consequent to the short half-life of drug.…”

“…If morning were to be undertaken, sampling time in relation to dose is critical because large interdose fluctuation in concentrations occur consequent to the short half-life of drug. Because serum TGB are in the nanomolar range, analytical methods are not simple and interlaboratory differences in analytical reliability is of great concern [207]. Several GC [208] and LC method with various detectors such as ECD [209] or MS [206] are available.…”

Therapeutic Drug Monitoring of Antiepileptic Medications

“…However, a clear relationship between tiagabine serum/plasma concentration and therapeutic efficacy has not yet been established, with a broad reference range of 20-200 ng/mL proposed (Patsalos et al, 2008;Uthman et al, 1998). For measurement of free drug concentrations, analytical sensitivity is an issue, with some assays having insufficiently low limits of sensitivity to measure clinically relevant free drug concentrations (Williams et al, 2003). Consequently, such analysis is only performed at specialized reference laboratories.…”