Tobramycin pharmacokinetics in children with febrile neutropenia undergoing stem cell transplantation: once-daily versus thrice-daily administration.
OBJECTIVE
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.


METHODS
Pharmacokinetic analysis of a randomized controlled trial.


METHODS
The Hospital for Sick Children, Toronto, Ontario, Canada.


METHODS
Sixty children (< 18 yrs) with febrile neutropenia undergoing stem cell transplantation.


METHODS
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; > or = 12 yrs, 7 mg/kg/dose) every 24 hours.


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 (Cmax) 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 (kel) 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 kel 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.


CONCLUSIONS
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.
Dupuis
L Lee
LL
Department of Pharmacy, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada. lee.dupuis@sickkids.ca
Sung
Lillian
L
Taylor
Tracey
T
Abdolell
Mohamed
M
Allen
Upton
U
Doyle
John
J
Taddio
Anna
A
D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009503:Neutropenia / Q000188:drug therapy / Q000378:metabolism* / Q000628:therapy; D033581:Stem Cell Transplantation; D014031:Tobramycin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000900:Anti-Bacterial Agents; D014031:Tobramycin