TY - JOUR
T1 - A Pharmacokinetic Analysis of Tobramycin in Patients Less than Five Years of Age with Cystic Fibrosis
T2 - Assessment of Target Attainment with Extended-Interval Dosing through Simulation
AU - Downes, Kevin J.
AU - Grim, Austyn
AU - Shanley, Laura
AU - Rubenstein, Ronald C.
AU - Zuppa, Athena F.
AU - Gastonguay, Marc R.
N1 - Funding Information:
Copyright © 2022 American Society for Microbiology. All Rights Reserved. Address correspondence to Kevin J. Downes, downeskj@email.chop.edu. The authors declare a conflict of interest. K.J.D. has received research support from Merck & Co., Inc. unrelated to the current work. A.F.Z. has received research support from Eunice Kennedy Shriver National Institute of Child Health & Human Development (award numbers UG1HD063108, R21HD093369), the U.S. Department of Defense (award number W81XWH-17-1-0668), and Zelda Therapeutics, unrelated to this work. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the above supporting agencies. All other authors: Nothing to declare. Received 17 December 2021 Returned for modification 26 January 2022 Accepted 7 April 2022 Published 28 April 2022
Funding Information:
K.J.D. has received research support from Merck & Co., Inc. unrelated to the current work. A.F.Z. has received research support from Eunice Kennedy Shriver National Institute of Child Health & Human Development (award numbers UG1HD063108, R21HD093369), the U.S. Department of Defense (award number W81XWH-17-1-0668), and Zelda Therapeutics, unrelated to this work. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the above supporting agencies.
Funding Information:
This study was carried out as part of our routine work. K.J.D. is supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number K23HD091365.
Publisher Copyright:
© 2022 American Society for Microbiology.
PY - 2022/5
Y1 - 2022/5
N2 - Extended interval dosing of tobramycin is recommended for treatment of pulmonary exacerbations in adults and older children with cystic fibrosis (CF), but data are limited in patients less than 5 years of age. We performed a retrospective population pharmacokinetic (PK) analysis of hospitalized children with CF ,5 years of age prescribed intravenous tobramycin for a pulmonary exacerbation from March 2011 to September 2018 at our hospital. Children with normal renal function who had ≥1 tobramycin concentration available were included. Nonlinear mixed effects population PK modeling was performed using NONMEM using data from the first 48 h of tobramycin treatment. Monte Carlo simulations were implemented to determine the fraction of simulated patients that met published therapeutic targets with regimens of 10-15 mg/kg/day once-daily dosing. Fifty-eight patients received 111 tobramycin courses (range 1-9/patient). A two-compartment model best described the data. Age, glomerular filtration rate, and vancomycin coadministration were significant covariates on tobramycin clearance. The typical values of clearance and central volume of distribution were 0.252 L/hr/kg^0.75 and 0.308 L/kg, respectively. No once-daily regimens achieved all pre-specified targets simultaneously in .75% of simulated subjects. A dosage of 13 mg/kg/dose best met the predefined targets of Cmax .25 mg/L and AUC24 of 80-120 mg h/L. Based on our population PK analysis and simulations, once-daily dosing of tobramycin would not achieve all therapeutic goals in young patients with CF. However, extended-interval dosing regimens may attain therapeutic targets in the majority of young patients.
AB - Extended interval dosing of tobramycin is recommended for treatment of pulmonary exacerbations in adults and older children with cystic fibrosis (CF), but data are limited in patients less than 5 years of age. We performed a retrospective population pharmacokinetic (PK) analysis of hospitalized children with CF ,5 years of age prescribed intravenous tobramycin for a pulmonary exacerbation from March 2011 to September 2018 at our hospital. Children with normal renal function who had ≥1 tobramycin concentration available were included. Nonlinear mixed effects population PK modeling was performed using NONMEM using data from the first 48 h of tobramycin treatment. Monte Carlo simulations were implemented to determine the fraction of simulated patients that met published therapeutic targets with regimens of 10-15 mg/kg/day once-daily dosing. Fifty-eight patients received 111 tobramycin courses (range 1-9/patient). A two-compartment model best described the data. Age, glomerular filtration rate, and vancomycin coadministration were significant covariates on tobramycin clearance. The typical values of clearance and central volume of distribution were 0.252 L/hr/kg^0.75 and 0.308 L/kg, respectively. No once-daily regimens achieved all pre-specified targets simultaneously in .75% of simulated subjects. A dosage of 13 mg/kg/dose best met the predefined targets of Cmax .25 mg/L and AUC24 of 80-120 mg h/L. Based on our population PK analysis and simulations, once-daily dosing of tobramycin would not achieve all therapeutic goals in young patients with CF. However, extended-interval dosing regimens may attain therapeutic targets in the majority of young patients.
KW - antibiotics
KW - pediatrics
KW - population pharmacokinetics
KW - therapeutic drug monitoring
UR - http://www.scopus.com/inward/record.url?scp=85130387052&partnerID=8YFLogxK
U2 - 10.1128/aac.02377-21
DO - 10.1128/aac.02377-21
M3 - Article
C2 - 35481751
AN - SCOPUS:85130387052
SN - 0066-4804
VL - 66
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 5
ER -