Prediction of sotalol‐induced maximum steady‐state QT c 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. Clinical Pharmacology and Therapeutics (1992) 52, 417–426; doi: 10.1038/clpt.1992.165