Abstract：
Amiodarone and mexiletine are used for ventricular arrhythmias, for which a combination therapy of both anti-arrhythmic drugs (AADs) is not uncommon. Therapeutic drug monitoring (TDM) can be beneficial for clinical guidance of therapy, especially to correctly identify adverse events. Desethylamiodarone, the active metabolite of amiodarone, accumulates over time and is associated with serious adverse events. Therefore, simultaneous TDM for amiodarone, desethylamiodarone and mexiletine is advantageous in clinical practice. The presented LC-MS/MS method was validated for selectivity, matrix effect, linearity, accuracy, precision, carry-over and stability. The method was continuously evaluated during eight months of clinical use. The method was shown to be linear within the measured range of 0.1 to 10 mg/L for each component. The matrix effect was considered negligible. No interfering responses were found for amiodarone, desethylamiodarone and the isotopic-labeled internal standards. A constant and reproducible within-run contribution of 45.3 %, originating from the system, was identified for mexiletine. The systemic contribution to the peak area of the lowest quantifiable concentration of mexiletine affected the selectivity and carry-over effect measurements. Multiple measurements showed that regression adjusted concentrations were accurate and reproducible, indicating calibration correction was applicable. Sample stability was found to be within limits for all storage conditions and freeze-thaw cycles. Furthermore, long-term method evaluation with external controls resulted in stable measurements with a percentage coefficient of variance between 1.3 % and 6.3 %. The presented practical and reliable method is applicable for clinical TDM and will allow clinical practitioners to guide drug therapy of amiodarone and mexiletine.
摘要：
胺碘酮和美西律用于室性心律失常，两种抗心律失常药物（AAD）的联合治疗并不少见。治疗药物监测(TDM)有利于临床指导治疗,尤其是正确识别不良事件。去乙基胺碘酮,胺碘酮的活性代谢产物,随着时间的推移积累，并与严重不良事件有关。因此,胺碘酮的同时TDM，去乙胺碘酮和美西律在临床实践中是有利的。对所提出的LC-MS/MS方法进行了选择性验证，基体效应，线性度准确度,精度,结转和稳定性。该方法在临床使用八个月期间连续评估。该方法在每种组分0.1至10mg/L的测量范围内显示为线性。基质效应被认为是可以忽略的。没有发现胺碘酮的干扰反应，去乙胺碘酮和同位素标记的内标。恒定且可重复的运行内贡献为45.3%，源于系统，被鉴定为美西律。对美西律最低可定量浓度的峰面积的系统贡献影响了选择性和残留效应测量。多次测量表明，回归调整后的浓度是准确和可重复的，表明校准校正适用。发现样品稳定性在所有储存条件和冻融循环的限度内。此外，使用外部对照的长期方法评估可获得稳定的测量结果,方差百分比系数在1.3%至6.3%之间.提出的实用可靠的方法适用于临床TDM，并将使临床医师指导胺碘酮和美西律的药物治疗。
