Primary standardization of assays for anticonvulsant drugs: comparison of accuracy and precision.
BACKGROUND
The accuracy and precision of methods for the measurement of the anticonvulsants phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide, and valproate in human serum were assessed in 297 laboratories that were participants in the United Kingdom National External Quality Assessment Scheme (UKNEQAS).


METHODS
We distributed lyophilized, serum-based materials containing low, medium, and high weighed-in concentrations of the drugs. The 297 participating laboratories received the materials on two occasions, 7 months apart. Expected concentrations were determined by gas chromatography or HPLC methods in five laboratories using serum-based NIST reference materials as calibrators.


RESULTS
In general, bias was consistent across concentrations for a method but often differed in magnitude for different drugs. Bias ranged from -1.9% to 8.6% for phenytoin, -2.7% to 3.1% for phenobarbital, -2.7% to 0.5% for primidone, -8.6% to 0.3% for carbamazepine, -5.6% to 2.0% for ethosuximide, and -7.2% to 0.1% for valproate. Intralaboratory sources of imprecision significantly exceeded interlaboratory sources for many drug/method combinations. The mean CVs for intra- and interlaboratory errors for the different drugs were 6.3-7.8% and 3.3-4.2%, respectively.


CONCLUSIONS
For these long-established and relatively high-concentration analytes, the closed analytical platforms generally performed no better than open systems or chromatography, where use of calibrators prepared in house predominated. To improve the accuracy of measurements, work is required principally by the manufacturers of immunoassays to ensure minimal calibration error and to eliminate batch-to-batch variability of reagents. Individual laboratories should concentrate on minimizing dispensing errors.
Wilson
John F
JF
Department of Pharmacology, Therapeutics & Toxicology, University of Wales College of Medicine, Cardiff CF14 4XN, United Kingdom. wilsonjf@cardiff.ac.uk
Watson
Ian D
ID
Williams
John
J
Toseland
Pat A
PA
Thomson
Alison H
AH
Sweeney
Grace
G
Smith
Brian L
BL
Sandle
Lance N
LN
Ramsey
John D
JD
Capps
Nigel E
NE
D000927:Anticonvulsants / Q000097:blood* / Q000592:standards; D002849:Chromatography, Gas; D002851:Chromatography, High Pressure Liquid; D019411:Clinical Laboratory Techniques / Q000592:standards*; D006801:Humans; D012015:Reference Standards; D012680:Sensitivity and Specificity
D000927:Anticonvulsants