title: Pharmacokinetic and pharmacodynamic optimisation of intravenous tobramycin dosing among children with cystic fibrosis.
abstract: This study aimed to characterize the pharmacokinetics of tobramycin administered one, two, or three times daily and to develop an optimal dosing scheme for children with cystic fibrosis. Therapeutic drug monitoring data were obtained from children hospitalized at three academic medical centres from 2006 to 2012. Population pharmacokinetic models were constructed using NONMEM 7.2. Model-based simulations were performed in Matlab R2012b to identify optimal dosing regimens using pharmacodynamic targets. The pharmacokinetic analysis involved 257 patients with a median age of 8.1 years (range 0.1-18.8). Clearance was estimated as 5.59 L/h and the volume of distribution was 18.90 L. Mean (±SD) maximum serum concentrations were highest among patients dosed once per day (24.1 ± 8.9 μg/mL) and were lower among patients dosed two and three times per day (11.2 ± 1.4 and 8.1 ± 2.4 μg/mL, respectively). Simulations revealed that once daily dosing was the only effective regimen for a Pseudomonas aeruginosa MIC of 1.5 μg/mL and none of the tested regimens reliably achieved the pharmacodynamic target for MICs ≥2 μg/mL. Once daily dosing resulted in higher maximum serum concentrations when compared to multiple-daily dosing. In simulations, once daily dosing was the only regimen to achieve the pharmacodynamic target for all subjects with MICs <2 μg/mL.
authors.affiliation: Department of Paediatrics, University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT, 84108, USA, catherine.sherwin@hsc.utah.edu.
authors.forename: Catherine M T
authors.initials: CM
authors.lastname: Sherwin
authors.forename: Jeffery T
authors.initials: JT
authors.lastname: Zobell
authors.forename: Chris
authors.initials: C
authors.lastname: Stockmann
authors.forename: Bradley E
authors.initials: BE
authors.lastname: McCrory
authors.forename: Millie
authors.initials: M
authors.lastname: Wisdom
authors.forename: David C
authors.initials: DC
authors.lastname: Young
authors.forename: Jared
authors.initials: J
authors.lastname: Olson
authors.forename: Krow
authors.initials: K
authors.lastname: Ampofo
authors.forename: Michael G
authors.initials: MG
authors.lastname: Spigarelli
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D007275:Injections, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests / Q000379:methods; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D014031:Tobramycin / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D014031:Tobramycin