Pharmacokinetics and pharmacodynamics of sotalol in a pediatric population with supraventricular and ventricular tachyarrhythmia.

Abstract

OBJECTIVE:

This pharmacokinetic-pharmacodynamic study was designed to define the steady-state relationship between pharmacologic response and dose or concentration of sotalol in children with cardiac arrhythmias, with an emphasis 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 patients 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 the QT and R-R intervals, respectively, of the surface electrocardiogram, which was recorded at 6 scheduled times before and after the third, sixth, and ninth doses. During these three dose intervals, 4 scheduled blood samples were also collected. Drug concentrations were measured with a validated nonstereoselective liquid chromatographic tandem mass spectrometric detection assay. Pharmacokinetic and pharmacodynamic parameters were obtained with standard methods.

RESULTS:

Twenty-one centers enrolled 25 patients in the study: 7 were neonates, 9 were infants, and 11 were children between the ages of 2 years and 12 years. The area under the drug concentration-time curve increased proportionately with dose. The apparent oral clearance of sotalol was linearly correlated with body surface area and creatinine clearance. The smallest children (body surface area <0.33 m2) 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 (+/- standard deviation) maximum increase for the QTc interval was 14% +/- 7% and the average Class III 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 beta-blocking effect during a dose interval was 12% +/- 13%. The effects tended to be larger in the smallest children. The Class III response and the plasma concentrations of sotalol were linearly related. The treatment was well tolerated.

CONCLUSIONS:

The steady-state pharmacokinetics of sotalol were dose proportionate. Pharmacologically important beta-blocking effects were observed at the 30-mg/m2 and 70-mg/m2 dose levels. Important Class III effects were seen at the 70-mg/m2 dose level. The Class III effect was linearly related to the drug concentration.

• Authors: J P Saul, B Ross, M S Schaffer, L Beerman, A P Melikian, J Shi, J Williams, J T Barbey, J Jin, P H Hinderling, Pediatric Sotalol Investigators
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 69 Issue 3 Pg. 145-57 (Mar 2001) ISSN: 0009-9236 [Print] United States
• PMID: 11240979 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Sotalol

Topics

• Anti-Arrhythmia Agents (pharmacology, therapeutic use)
• Area Under Curve
• Child
• Child, Preschool
• Dose-Response Relationship, Drug
• Electrocardiography (drug effects)
• Female
• Humans
• Infant
• Infant, Newborn
• Male
• Metabolic Clearance Rate
• Sotalol (pharmacokinetics, pharmacology, therapeutic use)
• Tachycardia, Supraventricular (drug therapy, metabolism)
• Tachycardia, Ventricular (drug therapy, metabolism)