Abstract Body: Introduction: Amiodarone (Amio) is a first-line medical therapy for ventricular arrhythmia. If patients do not respond to Amio or experience significant side-effects, mexiletine (Mex), a class Ib anti-arrhythmic agent, is often prescribed in addition to or in lieu of Amio. Both drugs undergo extensive metabolism, resulting in several active metabolites. The nonlinear effects of Amio and Mex interaction on the action potential significantly impacts whether the combined therapy is effective in treating patients with refractory ventricular arrhythmias.
Hypothesis: The plasma concentrations of Mex, Amio, and their active metabolites influence changes in QRS and QTc, markers for ventricular arrhythmia risk.
Methods: Patients recently or chronically prescribed Mex, including those concurrently receiving Amio, were enrolled. Plasma drug and metabolite concentrations were determined. Pre- and post-Mex ECG parameters were collected. Neural network models were constructed to predict post-Mex QRS and QTc using combinations of pre-Mex QRS and QTc, as well as drug and metabolite concentrations, as input variables.
Results: 71 patients were enrolled in the study. 18 patients started Mex within 48 hours of enrollment, 53 were prescribed Mex for > 1 month prior, and 51 were also prescribed Amio.
Plasma concentrations varied (median [range] in microgram/L): Mex 603 [0-2000], hydroxymethyl-Mex 65 [0-363], m-hydroxy-Mex 44 [0-358], Amio 1105 [0-22100], N-monodesethyl-Amio 920 [0-2060], and N,N-didesethyl-Amio 57 [0-129].
Baseline models using pre-Mex QTc and QRS values modestly predicted post-Mex QTc (R² = 0.26) and QRS (R² = 0.16). However, adding Amio and its metabolite concentrations enhanced the predictions (R² = 0.27 for QTc, 0.22 for QRS). Similarly, including Mex and its metabolite concentrations improved the predictions (R² = 0.28 for QTc, 0.20 for QRS). Notably, adding both Mex, Amio, and their metabolites synergistically boosted the predictions (R² = 0.32 for QTc, 0.28 for QRS).
Conclusion: Synergistic improvement in model to predict changes in QRS and QTc when using Mex, Amio, and their metabolite concentration implies nonlinear therapeutic interaction, showing that the combined therapy is not additive. Future work should investigate the therapeutic implications of this interaction.