PREDICTION OF SOTALOL-INDUCED MAXIMUM STEADY-STATE QTC PROLONGATION FROM SINGLE-DOSE ADMINISTRATION IN HEALTHY-VOLUNTEERS

The relationship between racemic sotalol plasma concentrations and QT(c) interval prolongation after both single-dose and repeated administration of three sotalol oral doses was studied in a randomized crossover protocol performed in 10 healthy volunteers. QT(c) interval increase was significant after the three single-dose sotalol administrations and was significantly related to the administered dose (p < 0.0001). In 21 of 30 analyses, QT(c) interval was linearly correlated with sotalol plasma concentrations. After the 320 mg dose, the linear model was a best fit for 90% of the cases, and no hysteresis was observed. After repeated sotalol administration, 69 of 87 QT(c) interval measurements at steady state could be predicted from the plasma concentration versus effect relationship established after single-dose 320 mg administration. Seventeen of 18 errors (94%) corresponded to QT(c) intervals that were significantly lower than predicted. These findings suggest that a short-term individual linear model determined after a 320 mg test dose of sotalol allows a good prediction of expected maximal increase in QT(c) duration in healthy subjects.