Pharmacokinetic modelling to predict risk of ototoxicity with intravenous tobramycin treatment in cystic fibrosis

• Published in: Journal of antimicrobial chemotherapy 2021-10, Vol.76 (11), p.2923-2931
• Main Authors: Dong, Min, Rodriguez, Anna V, Blankenship, Chelsea A, McPhail, Gary, Vinks, Alexander A, Hunter, Lisa L
• Format: Article
• Language: English
• Subjects: Aminoglycosides - adverse effects; Anti-Bacterial Agents - adverse effects; Bayes Theorem; Cystic Fibrosis - complications; Cystic Fibrosis - drug therapy; Humans; Original Research; Ototoxicity; Tobramycin - adverse effects
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkab288

Abstract Introduction Further optimization of therapeutic drug monitoring (TDM) for aminoglycosides (AGs) is urgently needed, especially in special populations such as those with cystic fibrosis (CF), >50% of whom develop ototoxicity if treated with multiple courses of IV AGs. This study aimed to empirically test a pharmacokinetic (PK) model using Bayesian estimation of drug exposure in the deeper body tissues to determine feasibility for prediction of ototoxicity. Materials and methods IV doses (n = 3645) of tobramycin and vancomycin were documented with precise timing from 38 patients with CF (aged 8–21 years), including total doses given and total exposure (cumulative AUC). Concentration results were obtained at 3 and 10 h for the central (C1) compartment. These variables were used in Bayesian estimation to predict trough levels in the secondary tissue compartments (C2 trough) and maximum concentrations (C2max). The C1 and C2 measures were then correlated with hearing levels in the extended high-frequency range. Results Patients with more severe hearing loss were older and had a higher number of tobramycin C2max concentrations >2 mg/L than patients with normal or lesser degrees of hearing loss. These two factors together significantly predicted average high-frequency hearing level (r = 0.618, P