Pharmacokinetics and pharmacodynamics of sotalol in a pediatric populationwith supraventricular and ventricular tachyarrhythmia

Objective: This pharmacokinetic-pharmacodynamic study was designed to defin e the steady-state relationship between pharmacologic response and dose or concentration of sotalol in children with cardiac arrhythmias, with an emph asis on neonates and infants. Methods: The treatment consisted of an upward titration with unit doses of 10, 30, and 70 mg of sotalol per square meter of body surface area. The pat ients received 3 doses at each dose level. The dosing interval was 8 hours. The Class III and beta -blocking activities of sotalol were derived from t he QT and R-R intervals, respectively, of the surface electrocardiogram, wh ich was recorded at 6 scheduled times before and after the third, sixth, an d ninth doses. During these three dose intervals, 4 scheduled blood samples were also collected. Drug concentrations were measured with a validated no nstereoselective liquid chromatographic tandem mass spectrometric detection assay. Pharmacokinetic and pharmacodynamic parameters were obtained with s tandard methods. Results: Twenty-one centers enrolled 25 patients in the study: 7 were neona tes, 9 were infants, and 11 were children between the ages of 2 years and 1 2 years. The area under the drug concentration-time curve increased proport ionately with dose. The apparent oral clearance of sotalol was linearly cor related with body surface area and creatinine clearance. The smallest child ren (body surface area <0.33 m(2)) displayed greater drug exposure than the larger children. The increase of QTc and R-R intervals was dose dependent. At the 70-mg/m(2) dose level, the mean (Ir standard deviation) maximum inc rease for the QTc interval was 14% <plus/minus> 7% and the average Class II I effect during a dose interval was 7% +/- 5%. At the same dose level, the mean maximum increase of the R-R interval was 25% +/- 15% and the average b eta -blocking effect during a dose interval was 12% +/- 13%. The effects te nded to be larger in the smallest children. The Class III response and the plasma concentrations of sotalol were linearly related. The treatment was w ell tolerated. Conclusions: The steady-state pharmacokinetics of sotalol were dose proport ionate. Pharmacologically important beta -blocking effects were observed at the 30-mg/m(2) and 70-mg/m(2) dose levels. Important Class III effects wer e seen at the 70-mg/m2 dose level. The Class III effect was linearly relate d to the drug concentration.