A pharmacokinetic-pharmacodynamic model of d-sotalol Q-Tc prolongation during intravenous administration to healthy subjects

The objective of this study was to assess the pharmacokinetics and pharmacodynamics of the dextro (d-) isomer of sotalol, a class III antiarrhythmic agent, in healthy young men and women after a single intravenous bolus dose. The design was open-label, randomized, parallel group. Each group (4 men and 4 women) received either 0.5, 1.5, or 3.0 mg/kg d-sotalol as an intravenous infusion for 2 minutes. Serial measurements of the d-sotalol plasma concentration and the Q-Tc interval data were recorded before, during, and for 72 hours after drug administration. The pharmacokinetics of d-sotalol were found to be well described by a three-compartment model with linear elimination clearance from the central compartment. There were no significant differences in the elimination clearance or volume of the central compartment between dose levels or between men and women. However, women were found to have a lower steady-state volume of distribution than men (1.20 L/Kg versus 1.43 L/Kg). The Q-Tc versus d-sotalol plasma concentration data were fitted to a model that assumed a distinct "effect compartment" and sigmoidal Emax response. The baseline Q-Tc, determined from the fittings, was found to be significantly higher in women (0.40 versus 0.38 seconds). The effect compartment clearance was found to be highly variable, with a median of 12.3 (range, 0.2-671,300) L/h. There were statistically significant differences in the effect compartment clearance by dose among men and by gender at a dose of 1.5 mg/kg. There were no significant differences detected between dose groups or genders for the d-sotalol effect site concentration at one half the maximum Q-Tc prolongation from baseline (EC50), EMAX, (the maximum Q-Tc prolongation from baseline) or the Hill coefficient. In conclusion, the pharmacokinetics of d-sotalol after intravenous administration are independent of dose and gender, because the difference between men and women in volume of distribution at steady-state is not clinically significant. The pharmacodynamics of Q-Tc prolongation produced by d-sotalol appear to be independent of dose and gender; however, there is considerable variability in the time course of effects on Q-Tc between individuals.
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