Pharmacokinetic/pharmacodynamic analysis of weight- and height-scaled tobramycin dosage regimens for patients with cystic fibrosis

S. S. Alghanem, D. J. Touw, A. H. Thomson

Research output: Contribution to journalArticle

3 Downloads (Pure)

Abstract

OBJECTIVES: To determine the outcomes of weight- and height-based tobramycin dosing regimens for patients with cystic fibrosis (CF). METHODS: A simulated dataset of 5000 patients based on 331 patients with CF was created using NONMEM. Pharmacokinetic (PK) parameters were derived for each patient from a published model using Monte Carlo simulation. The abilities of 10 and 12 mg/kg/day and 3 and 4 mg/cm/day to achieve standard and extended Cmax (20-30 and 20-40 mg/L) and AUC0-24 (80-120 and 80-150 mg·h/L) targets were evaluated. PK/pharmacodynamic (PK/PD) indices were a Cmax/MIC ratio ≥10 and an AUC0-24/MIC ratio ≥110. For these indices and a range of MICs, cumulative fractions of response (CFRs) for Pseudomonas aeruginosa were also determined. RESULTS: More patients achieved standard Cmax and AUC0-24 targets with 3 mg/cm/day (64% and 62%, respectively) than with 10 mg/kg/day (43% and 48%, respectively). AUC0-24 estimates >120 mg·h/L were more common with weight-based dosing. With higher doses, 72% achieved high target peaks with 4 mg/cm/day and 65% with 12 mg/kg/day. For the Cmax/MIC index, the maximal MIC for the target microorganism was 2 mg/L with lower doses, 2.5 mg/L with higher doses and 0.5 mg/L for AUC0-24/MIC-based regimens. The CFR for all regimens was >90% for Cmax targets and 66% to 79% for AUC0-24 targets. CONCLUSIONS: A tobramycin dose of 3 mg/cm/day rather than 10 mg/kg/day achieved similar PK/PD outcomes but dose and AUC0-24 ranges were narrower and the incidence of high AUC0-24 values was lower. Height-based doses should therefore be considered for patients with CF.

Original languageEnglish
Pages (from-to)2311-2317
Number of pages7
JournalJournal of Antimicrobial Chemotherapy
Volume74
Issue number8
Early online date6 May 2019
DOIs
Publication statusPublished - 31 Aug 2019

Keywords

  • pharmacokinetics
  • pharmacodynamics
  • aminoglycosides
  • Monte Carlo Simulation

Cite this