Tobramycin Pharmacokinetics in Children with Febrile Neutropenia Undergoing Stem Cell Transplantation: Once-Daily versus Thrice-Daily Administration

Study Objectives. To describe the pharmacokinetic disposition of tobramycin in children undergoing stem cell transplantation (SCT) after intravenous administration either every 24 hours or every 8 hours, and to use this information to create initial dosing guidelines for administration every 24 hours in this patient population. Design. Pharmacokinetic analysis of a randomized controlled trial. Setting. The Hospital for Sick Children, Toronto, Ontario, Canada. Patients. Sixty children (< 18 yrs) with febrile neutropenia undergoing stem cell transplantation. Intervention. Patients were randomized to receive intravenous tobramycin either every 24 hours (29 patients) or every 8 hours (31 patients). Initially, they received either 2.5 mg/kg/dose every 8 hours or weight-based doses by age group (< 5 yrs, 9 mg/kg/dose; 5 to < 12 yrs, 8 mg/kg/dose; ≥ 12 yrs, 7 mg/kg/dose) every 24 hours. Measurements and Main Results. Serum tobramycin concentrations were obtained at 2 and 8 hours after the first dose. Initial guidelines for dosing every 24 hours were derived using the parameters from all patients to achieve a maximum serum concentration (C_max) of 20-22.5 mg/L and a drug-free interval (time during dosing interval when the tobramycin concentration was < 1 mg/L) of at least 4 hours. After the first tobramycin dose, the elimination rate constant (k_el) and volume of distribution (Vd) observed in the every-8-hour group (23 patients) were 0.34 ± 0.09 hours^-1 and 0.48 ± 0.21 L/kg, respectively. The k_el and Vd in the every-24-hour group (22 patients) were 0.43 ± 0.12 hr^-1 and 0.43 ± 0.26 L/kg, respectively. Tobramycin Vd varied with age. Initial doses of tobramycin every 24 hours recommended to achieve the target parameters are 10 mg/kg/dose for patients aged 6 months to less than 9 years, 8 mg/kg/dose for those aged 9 to less than 12 years, and 6 mg/kg/dose for those aged 12 years or older. Conclusion. Children undergoing SCT who receive tobramycin every 24 hours should receive an initial dose based on age. Further validation of the proposed dosing guidelines is required.