Developing a safe intravenous sotalol dosing regimen

Recently, an intravenous formulation of sotalol has been approved by the food and drug administration for substitution for oral therapy in patients who are unable to take oral sotalol. The purpose of this randomized, 2-treatment, 2-period, crossover study was to develop a safe dosing regimen for intravenous sotalol that provides similar blood levels and therefore similar efficacy and safety to orally administered sotalol. Fifteen healthy subjects received 75 mg intravenous sotalol infusion administered over 2.5 hours and 80 mg oral sotalol. Standard pharmacokinetic methods were used to obtain maximum serum concentrations (Cmax) and areas under the concentration-time curves (AUC). Individual pharmacokinetic parameters were used in simulation studies to determine the optimal intravenous administration regimen. Intravenous sotalol administered over 2.5 hours resulted in a significantly greater Cmax than oral administration (830 +/- 391 vs. 601 +/- 289 ng/mL, P < 0.001). With increasing the length of infusions to 3, 4, and 5 hours, simulation studies showed that the Cmax decreased to 128%, 113%, and 102% of the oral Cmax. The length of infusion did not affect AUC. Based on these studies, a safe intravenous regimen for the replacement of 80-mg oral therapy requires 75 mg intravenous sotalol administered as a 5-hour infusion. Because the pharmacokinetics of sotalol are linear and dose proportional, 150 mg intravenous sotalol administered over 5 hours will provide similar Cmax and AUC as 160 mg oral sotalol. The food and drug administration-approved dosing regimen is 75 mg intravenous sotalol to replace 80 mg oral sotalol and 150 mg intravenous sotalol to replace 160 mg oral sotalol, both administered over 5 hours

QT Prolongation and Serum Sotalol Concentration Are Highly Correlated following Intravenous and Oral Sotalol

Objectives: The aim of this study was to evaluate the correlation between QT interval (QT) and serum sotalol concentration following a single low dose of oral and intravenous sotalol. Methods: Fifteen healthy volunteers received 75 mg intravenous sotalol over 2.5 h and 80 mg oral sotalol in a random order. Serum sotalol concentrations and 12-lead electrocardiograms were obtained simultaneously at baseline and 7 times following dosings. Rate-corrected QT (QTc) was calculated by the Bazett, Fridericia and Framingham formulas. Linear regression analysis was performed between sotalol concentrations and QT measurements. Results: Significant QT prolongation was seen at very low sotalol doses and serum concentrations. QTc intervals calculated by the Framingham and Fridericia formulas showed the strongest and virtually identical correlations with serum sotalol concentration (r ≧ 0.97, p < 0.001) following oral and intravenous administrations. The equation QTc = 0.0342 (sotalol concentration) + 398 closely predicted actual QTc at any sotalol concentration. Conclusions: A strong correlation was observed between serum sotalol concentration and QTc prolongation across the entire concentration range. Low-dose sotalol caused significant QT prolongation. At similar concentrations, intravenous and oral sotalol caused similar QT and QTc effects. Knowing the QT effect can be used to guide further dose increase

Gender differences in cardiac repolarization following intravenous sotalol administration

Females are more susceptible to drug-induced torsade de pointes (TdP), which is associated with excessive prolongation of the heart rate-corrected QT interval (QTc). Sotalol prolongs the cardiac action potential that can be observed as QT prolongation and can induce TdP. The aim of this study was to assess gender differences in sotalol-induced QTc prolongation. A total of 15 healthy volunteers, 9 female and 6 male (age: 32 ± 8 years) received 75 mg intravenous sotalol over 2.5 hours at a constant infusion rate. A 12-lead electrocardiograph (ECG) was recorded at baseline, 0.5, 1, 2, 3, 4, and 5 hours following the start of the infusion, and blood samples were collected simultaneously. QTc was calculated by the Fridericia and Framingham formulas. The 2 formulas resulted in virtually identical QTc intervals. The data analysis included repeated measures of analysis of variance (ANOVA), univariate analysis, and linear regression analysis. The longest average QTc intervals were observed at 2 hours of sotalol infusion in both genders. Compared to baseline, the increase was very significant in females (411 ± 13 vs 438 ± 13 ms, P < .001), while it was less significant in males (395 ± 23 vs 413 ± 27 ms, P < .05). The magnitude of individual changes from baseline were greater in females than in males (34 ± 8 vs 21 ± 12 ms, P < .05). In each gender, QTc and serum sotalol concentration strongly correlated (r = .93, P < .001). An upward shift of the regression line in females indicates a longer QTc at any concentration level. Males had greater body weight and body surface area than females (P < .05) but neither correlated with QTc or predicted QTc prolongation. The univariate analysis indicated that the single predictor for the greater QTc prolongation was female gender. Females had greater QTc prolongation than males following sotalol administration. This enhanced response to drug action may explain the higher incidence of drug-induced TdP seen in females