TOLERANCE TO THE REPOLARIZATION EFFECTS OF RAC-SOTALOL DURING LONG-TERM TREATMENT

Aims To establish whether tolerance to the QT effect could ensue durin g maintenance treatment with rac-sotalol. Methods The effect of rac-so talol 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 rel ationship was preliminarly assessed in each patient after the administ ration of a pure beta-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 he art rate/QT relationship. Results In all patients QT interval prolonga tion was linearly correlated with rac-sotalol log plasma concentration . The maximal QT prolongation and peak plasma concentration were not s ignificantly 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(-1) vs 1.83+/-0.66 mg l(-1)). Line slopes were also unchanged fol lowing chronic treatment (21.8+/-8.4 vs 21.1+/-9.2). In four cases a s ignificant rightward shift of the line occurred during repeated admini strations, consistent with the appearance of pharmacodynamic tolerance . The inconstancy of this change in responsiveness may either be ascri bed to a genetically determined individual susceptibility or to a vari able interplay between Class III effect, gradual QT prolongation due t o long-term beta-adrenoceptor blockade and tolerance development. Conc lusions During maintenance treatment with rac-solatol, partial loss of repolarization effects occurred in sc,me patients suggesting pharmaco logical tolerance.