Tolerance to the repolarization effects of ‘oorac‘ox‐sotalol during long‐term treatment

Aims To establish whether tolerance to the QT effect could ensue during maintenance treatment with rac-sotalol. Methods The effect of rac-sotalol on QT interval duration was studied in 10 patients after single oral administration (160 mg) and after 6-day multiple oral dosing (80 mg two or three times daily). In order to separate the pure Class III effect from the bradycardia-related QT prolongation, heart rate/QT relationship was preliminarly assessed in each patient after the administration of a pure b-adrenoceptor blocker (propranolol, 80 mg orally). Repolarization changes were quantified as percent difference between the measured QT and the expected QT on the basis of the individual heart rate/QT relationship. Results In all patients QT interval prolongation was linearly correlated with rac-sotalol log plasma concentration. The maximal QT prolongation and peak plasma concentration were not significantly different following acute and chronic administrations (QT effect: +18.1±6.3%vs +14.2±3.3%; peak concentration: 1.64±0.49 mg l−1vs 1.83±0.66 mg l−1 ). Line slopes were also unchanged following chronic treatment (21.8±8.9 vs 21.1±9.2). In four cases a significant rightward shift of the line occurred during repeated administrations, consistent with the appearance of pharmacodynamic tolerance. The inconstancy of this change in responsiveness may either be ascribed to a genetically determined individual susceptibility or to a variable interplay between Class III effect, gradual QT prolongation due to long-term b-adrenoceptor blockade and tolerance development. Conclusions During maintenance treatment with rac-solatol, partial loss of repolarization effects occurred in some patients suggesting pharmacological tolerance.