Abstract
Aims: To derive useful pharmacokinetic (PK) and pharmacodynamic (PD) information for guiding the clinical use of sotalol in pediatric patients with supraventricular (SVT) or ventricular tachyarrhythmia (VT).
Methods: Two studies were conducted in-patients with SVT or VT in the age range between birth and 12 years old. Both studies used an extemporaneously compounded formulation prepared from sotalol HCl tablets. In the PK study, following a single dose of 30 mg/m2 sotalol, extensive blood samples (n=10) were taken. The PK–PD study used a dose escalation design with doses of 10, 30, and 70 mg/m2, each administered three times at 8-hr intervals without a washout. Six ECG recordings for determination of QT and RR were obtained prior to the initial dose of sotalol. Four blood samples were collected six ECG's were determined during the third interval at each dose level. Plasma concentrations of sotalol (C) were assayed by LC/MS/MS. The data analysis used NONMEM to obtain the population PK and PD parameter estimates. The individual PK and PD parameters were estimated with empirical Bayes methodology.
Results: A total of 611 C from 58 patients, 477 QTc and 499 RR measurements from 23 and 22 patients, respectively, were available for analysis. The PK of sotalol was best described by a linear two-compartment model. Oral clearance (CL/F) and volume of central compartment (Vc/F) were linearly correlated with body surface area (BSA), body weight or age. CL/F was also linearly correlated with creatinine clearance. The best predictor for both CL/F and Vc/F was BSA. The remaining intersubject coefficients of variation (CV's) in CL/F, and Vc/F were 21.6% and 20.3%, respectively. The relationship of QTc to C was adequately described by a linear model. The intersubject CV's in slope (SL) and intercept (E0) were 56.2 and 4.7%, respectively. The relationship of RR to C was also adequately described by a linear model in which the baseline RR and SL were related to age or BSA. The intersubject CV's for SL and E0 were 86.7 and 14.4%, respectively.
Conclusions: BSA is the best predictor for the PK of sotalol. Both QTc and RR effects are linearly related to C. No covariates are found for the QTc–C relation, while the RR–C relation shows age or BSA dependency.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
The current labeling for Betapace®(sotalol HCl), In: Physicians' Desk Reference, 55th ed. Montvale (NJ): Medical Economics; 2001, pp. 905–908.
The current labeling for Betapace AFTM (sotalol HCl), In: Physicians' Desk Reference, 55th ed. Montvale (NJ): Medical Economics; 2001, pp. 908–912
P. Maragnes, M. Tipple, and A. Fournier. Effectiveness of oral sotalol treatment of pediatric arrhythmia. Am. J. Cardiol. 69:751–754 (1992).
J. P. Pfammatter, T. Paul, C. Lehmann, and H. C. Kallfelz. Efficacy and proarrhythmia of oral sotalol in pediatric patients. Am. Coll. Cardiol. 26:1002–1007 (1995).
R. E. Tanel, E. P. Walsh, J. A. Lulu, and J. P. Saul. Sotalol for refractory arrhythmias in pediatric and young adult patients: Initial efficacy and log-term outcome. Am. Heart J. 130:791–797 (1995).
G. C. M. Beaufort-Krol and M. T. E. Brink-Boelkens. Effectiveness of sotalol for atrial flutter in children after surgery for congenital heart disease. Am. J. Cardiol. 79:92–94 (1997).
J. J. Hanyok. Clinical pharmacokinetics of sotalol. Am. J. Cardiol. 72:19A–26A (1993).
J. T. Barbey, M. E. Sale, R. L. Woosley, J. Shi, A. P. Melikian, and P. H. Hinderling. Pharmacokinetic, pharmacodynamic, and safety evaluation of an accelerated dose titration regimen of sotalol in healthy middle-aged subjects. Clin. Pharmacol. Ther. 66:91–99 (1999).
S. L. Beal and L. B. Sheiner. The NONMEM system. Am. Statistician 34:118–119 (1980).
A. J. Boeckmann, L. B. Sheiner, and S. L. Beal. NONMEM Users Guide, NONMEM Project Group, University of California, San Francisco, 1994.
J. P. Saul, M. S. Schaffer, P. P. Karpavich, C. C. Erickson, J. Triedman, A. P. Melikian, J. Shi, A. Karara, B. Cai, and P. H. Hinderling. Single dose pharmacokinetics of sotalol in a pediatric population with supraventricular and_or ventricular tachyarrhythmia. J. Clin. Pharmacol. 41:35–43 (2000).
J. P. Saul, B. Ross, M. S. Schaffer, L. Beerman, A. P. Melikian, J. Shi, J. Williams, J. T. Barbey, J. Jin, and P. H. Hinderling. Pharmacokinetics and pharmacodynamics of sotalol in a pediatric population with supraventricular and ventricular tachyarrhythmia. Clin. Pharmacol. Ther. 69:145–57 (2001).
G. J. Schwartz, L. P. Brian, and A. Spitfire. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr. Clin. North Am. 34:571–590 (1987).
R. D. Mosteller. Simplified calculation of body-surface area. N. Engl. J. Med. 317:1098 (1987).
H. C. Bazett. An analysis of the time-relations of electrocardiograms. Heart 7:353–370 (1920).
A. Gelman, J. B. Carlin, H. S. Stern, and D. B. Rubin (eds.) Bayesian Data Analysis. London: Chapman and Hall, 1995.
T. R. Johnson, W. M. Moore, and J. E. Jeffries. Children are different: Deû elopmental Physiology, (2nd ed), Ross Laboratories, 1978.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Shi, J., Ludden, T.M., Melikian, A.P. et al. Population Pharmacokinetics and Pharmacodynamics of Sotalol in Pediatric Patients with Supraventricular or Ventricular Tachyarrhythmia. J Pharmacokinet Pharmacodyn 28, 555–575 (2001). https://doi.org/10.1023/A:1014412521191
Issue Date:
DOI: https://doi.org/10.1023/A:1014412521191