Variation with Time in Components of Variance for Measurements of Therapeutic Drugs

Analyses for therapeutic drugs are commonly made with automated, high-throughput, multichannel instruments that require minimal operator intervention. Performance monitoring of these assays is accomplished by means of internal and external (proficiency testing) quality-control procedures. Proficiency test schemes have demonstrated that the within-laboratory sources of variation are more important than between-laboratory sources (1)(2)(3), and the College of American Pathologists laboratory improvement program showed that the within-laboratory variance doubled for samples measured 4 months apart compared with measurements made at the same time (2). The present study was designed to track this decrease in within-laboratory precision over time to provide insights into the possible sources of imprecision in routine clinical measurements of therapeutic drugs in serum.A lyophilized proficiency test sample was prepared by adding midtherapeutic concentrations of 14 drugs to 5.9 L of human serum (Scipac Ltd.). Drug concentrations were as follows: phenytoin, 15.2 mg/L; phenobarbital, 30.3 mg/L; primidone, 7.1 mg/L; carbamazepine, 7.7 mg/L; carbamazepine 10,11-epoxide, 1.9 mg/L; ethosuximide, 68.1 mg/L; valproate, 76.8 mg/L; clonazepam, 42.0 μg/L; lamotrigine, 3.1 mg/L; theophylline, 15.0 mg/L; caffeine, 7.8 mg/L; digoxin, 1.2 μg/L; gentamicin, 2.7 mg/L; and lithium 0.76, mmol/L. The CV of dispensing of test sample aliquots by weight was 0.08%. We distributed 5 differently coded aliquots of the proficiency test sample, on 4 occasions, for analysis by members of the United Kingdom National External Quality Assessment scheme for drug assays. The scheme has an international membership of mostly hospital- or clinic-based sites, with 60% of their participants from the United Kingdom, 30% from Europe, and 10% outside Europe. A pair of samples was sent for analysis 1 month, and 3 single samples were sent at intervals to permit comparisons between pairs …