1. ¹Children's Heart Center, Medical University of South Carolina, Charleston, SC; Children's Hospital of the King's Daughter, Norfolk, Va; The Children's Hospital, Denver, Colo; Children's Hospital, Pittsburgh, Pa; and the Clinical Pharmacology Department, Berlex Laboratories Inc, Montville, NJ
2. ²University of Iowa, Iowa City
3. ³Columbus Children's Hospital, Columbus, Ohio
4. ⁴University of Michigan, Ann Arbor
5. ⁵Children's Hospital, Medical Center, Cincinnati
6. ⁶Arkansas Children's Hospital, Little Rock
7. ⁷Vanderbilt University, Nashville, Tenn
8. ⁸St Joseph's Children Hospital, Paterson, NJ, and Clinical Research Center, Mount Sinai School of Medicine, New York.
9. ⁹Texas Children's Hospital, Houston
10. ¹⁰Children's Mercy Hospital, Kansas City, Mo
11. ¹¹Duke University Medical Center, Durham, NC
12. ¹²Children's Hospital of Michigan, Detroit
13. ¹³Babies Hospital 2 N, Columbia Presbyterian Medical Center, New York
14. ¹⁴Children's Medical Center of Dallas, Texas
15. ¹⁵The Children's Heart Center, Atlanta, Ga
16. ¹⁶Children's Hospital of Philadelphia, Penn
17. ¹⁷Boston Children's Hospital, Mass
18. ¹⁸UCSF School of Medicine, Palo Alto, Calif
19. ¹⁹St Louis Children Hospital, Mo

Correspondence: Peter H. Hinderling, MD, PhD, Department of Clinical Pharmacology, Berlex Laboratories, Inc, 340 Changebridge Road, P.O. Box 1000, Montville, NJ 07045-1000 E-mail: Peter_Hinderling@berlex.com

^*Supported by Berlex Laboratories, Inc, Montville, NJ.

Received 19 June 2000; Accepted 12 December 2000.

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 -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/m² 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 -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 -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.