Interlaboratory Variability in the Quantification of New Generation Antiepileptic Drugs Based on External Quality Assessment Data *John Williams, *Meir Bialer, *Svein I. Johannessen, *Gu ¨ nther Kra ¨mer, *Rene ´ Levy, *Richard H. Mattson, *Emilio Perucca, *Philip N. Patsalos, and †John F. Wilson *Subcommission on Therapeutic Drug Monitoring and Pharmacokinetics, ILAE Commission on Therapeutic Strategies; and †Department of Pharmacology, Therapeutics and Toxicology, University of Wales College of Medicine, Heath Park, Cardiff, Wales 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 ox- carbazepine (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 chromatog- raphy 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 chro- matography showed poorer accuracy compared with immuno- assay and gas chromatography–mass spectrometry. Conclusions: With the notable exception of TGB, interlabo- ratory variability in the determination of new AEDs was com- parable 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. Participa- tion in an EQAS scheme is recommended to ensure adequate control of assay variability in therapeutic drug monitoring. Key Words: Felbamate—Gabapentin—Lamotrigine—Oxcarbaze- pine—Tiagabine—Topiramate—Vigabatrin—Drug assay— Therapeutic drug monitoring—External quality assessment. In the early 1970s, the realization that pharmacokinet- ic variability was a major factor affecting clinical re- sponse to antiepileptic drugs (AEDs) led to major improvements in the management of patients with epi- lepsy (1). In particular, awareness that steady-state con- centrations of AEDs can be influenced markedly by interpatient differences in genetic background (2), age (3), associated disease (4), and comedication (5) resulted in greater attention being given to tailoring drug dosage to meet individual requirements. Evidence also was ob- tained, at least for some drugs, that clinical response correlated better with serum drug concentration than with the prescribed daily dose, an observation that was crucial in establishing the value of therapeutic drug monitoring (TDM) as an aid to dosage adjustments (6,7). For TDM to be clinically useful, it is essential that drug concentrations be measured reliably. In the early days of TDM, analytic methods for the determination of AEDs in body fluids were less than desirable, and the accuracy and precision of individual laboratories in mea- suring patients’ samples was alarmingly poor (8–10). The situation, however, has improved markedly over the years because of a number of factors, including (a) in- creased awareness of the technical difficulties involved in drug assays; (b) advances in analytic technology, with special reference to the development of commercially available automated or semiautomated immunoassay; (c) Accepted August 17, 2002. Address correspondence and reprint requests to Dr. J. Williams at Department of Pharmacology, Therapeutics and Toxicology, Univer- sity of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, U.K. E-mail: Williamsj10@cf.ac.uk Epilepsia, 44(1):40–45, 2003 Blackwell Publishing, Inc. © International League Against Epilepsy 40