A simple, high-throughput LC-MS/MS method for the simultaneous quantification of four antiarrhythmic drugs and two metabolites: large-scale application to 622 patient samples

초록

Therapeutic drug monitoring (TDM) of antiarrhythmic drugs (AADs) remains underutilized in clinical practice despite the narrow therapeutic windows and marked inter-individual pharmacokinetic variability of these agents. Here, we developed and validated a simple, high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of four commonly prescribed AADs-amiodarone, dronedarone, flecainide, and propafenone-and two metabolites, noramiodarone and debutyldronedarone, in human serum, and applied it to routine clinical samples. Sample preparation consisted of simple protein precipitation using only 10 mu L of serum, with a 2 mu L injection volume and a total run time of 5.7 min. The method showed excellent linearity for all analytes (R-2 > 0.99), acceptable precision (%CV 0.9-5.9%) and accuracy (%bias -6.5-10.5%), minimal matrix effects (88.1-106.6%), satisfactory extraction recoveries (93.9-104.1%), and no significant carryover. No exogenous interference was observed from 25 commonly co-administered cardiovascular drugs, or from 45 neuropsychiatric drugs. The validated assay was successfully applied to 622 serum samples from 524 Korean patients with various arrhythmias. AAD concentrations showed substantial inter-individual variability at identical daily doses, and high proportions of samples were below the therapeutic ranges, supporting the potential utility of routine AAD TDM. This LC-MS/MS method provides a rapid, robust, and clinically practical platform for routine individualized AAD TDM in real-world serum samples with complex matrices.

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