Comparative Pharmacokinetic and Pharmacodynamic Properties of Oral and Intravenous (+)-Sotalol in Healthy Volunteers

Abstract— The pharmacokinetic and pharmacodynamic properties of (+)-sotalol (BMY-5763) were studied to analyse the relationship between plasma concentration and QT_c prolongation in healthy male volunteers given single oral doses of 50, 100, 200 and 300 mg, repeated oral doses of 200 mg twice daily for 6·5 days, and single intravenous doses of 1·0 and 1·5 mg kg^?1. The plasma concentration of (+)-sotalol peaked about 3 h after oral administration and declined with a half-life of 7·9–9·7 h. The C_max and AUC showed dose-related increases, while the urinary recovery as the unchanged form remained constant (66–68% of the dose). During repeated oral administration the plasma concentration of (+)-sotalol reached almost a steady state on the 3rd day and there was no change in renal clearance of (+)-sotalol measured on the 1st, 4th and 7th days. After intravenous administration, (+)-sotalol in plasma decreased biexponentially with a terminal half-life of 7·6–8·3 h and the urinary recovery as unchanged drug amounted to 84–88% of the dose. The increase in QT interval was significant after a single oral administration except for the lowest dose, and regression analysis revealed a significant correlation between QT_c interval and concentration of (+)-sotalol in plasma. The same correlation was evident with repeated oral doses on the 1st, 4th and 7th days. In the case of single intravenous administrations of (+)-sotalol, a combined pharmacokinetic-pharmacodynamic model was attempted by assuming an effect compartment. This analysis was shown to be effective to adjust the lag of effect behind a rapid change in plasma concentration which occurred in the early distributive phase because there was no evidence that the metabolite made any significant contribution to the effect of (+)-sotalol.