| Autor: |
Saul, J. Philip, Ross, Bertrand, Schaffer, Michael S., Beerman, Lee, Melikian, Armen P., Shi, Jun, Williams, John, Barbey, Jean T., Jin, Judy, Hinderling, Peter H., Atkins, Dianne, Chan, David, Dick, MacDonald, Epstein, Michael R., Erickson, Christopher, Fish, Frank A., Fishberger, Steven, Friedman, Richard, Hulse, J. Edward, Kanter, Ronald J., Karpawich, Peter, Pass, Robert, Scott, William, Strieper, Margret, Tanel, Ronn, Triedman, John, Van Hare, George F., Zimmerman, Frank |
| Zdroj: |
Clinical Pharmacology & Therapeutics; March 2001, Vol. 69 Issue: 3 p145-157, 13p |
| Abstrakt: |
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 β-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/m2dose 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 β-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 β-blocking effects were observed at the 30-mg/m2and 70-mg/m2dose levels. Important Class III effects were seen at the 70-mg/m2dose level. The Class III effect was linearly related to the drug concentration. |
| Databáze: |
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