JS Barrett (1,4), A Zuppa (1,3), M Schreiner (5) and PC Adamson (1, 2, 4)
(1) Division of Clinical Pharmacology; (2) Division of Oncology; (3) Division of Critical Care Medicine, The Children's Hospital of Philadelphia, (4) Pediatrics Department, College of Medicine, The University of Pennsylvania, (5) Children’s Clinical Research Institute, Philadelphia, PA
Introduction: Esmolol has recently been studied in two clinical trials from which population pharmacokinetics have been derived: ETHIC, “Esmolol In Pediatric Patients Undergoing Treatment of Hypertension in Infants and Children After Surgical Repair of Coarctation of the Aorta” and ESCAPE, “Esmolol In Pediatric Patients with Supraventricular Arrhythmias.”
Objectives: To describe esmolol pharmacokinetics in pediatric patients via population PK modeling and identify covariate, demographic and clinical factors that are important predictors of variability in esmolol PK parameters.
Methods: The ETHIC trial contained 107 patients: 22 newborns, 42 infants, and 43 children at doses of 125, 250, or 500 μg/kg/min after receiving a 125, 250, or 500 μg/kg respective bolus over 10-20 seconds. ESCAPE contained 34 patients, 3 to 17 years of age administered esmolol as a loading dose of 1000 mg/kg, immediately followed by an infusion of 300 mg/kg/min for 15 minutes. Dosing, covariate and PK data were merged across study and the final population PK database was comprised of 135 individual patients and 552 plasma esmolol concentration observations. Data was analyzed with NONMEM version 5 on a PC platform (Pentium IV; 2.6 GHz processor).
Results: The structural model was a two-compartment linear model with staged zero-order infusions. Inter-individual random variability was described by exponential variance for clearance (CL) and volume of distribution (Vd). Residual random variability was described by a combined additive and proportional variance model. Base model diagnostic plots revealed a large degree of unexplained variability. When an allometric model (fixed exponent of 0.75 for CL) was used to describe the change in PK parameters as a function of body weight, a significant improvement was evident. Race, sex, and age were also explored individually as covariates on clearance and volume. Population estimates of clearance and volume estimates were 10.2 L/hr and 9.96 L, which is similar to historical data on esmolol in pediatric populations.
Conclusions: The pediatric population PK model provided a robust description of esmolol PK across a wide range of ages (0.01 – 16.7 years) and body weights (2.6 – 114.1 kg). Model predictions were consistent with a linear, time-independent system. Newborns and infants appear to clear esmolol faster than children greater than 1 year of age. Clearance in children greater than 1 year of age is similar to that observed in adults.
Reference: PAGE 13 (2004) Abstr 490 [www.page-meeting.org/?abstract=490]
Poster: poster