Effects of CFTR modulators on pharmacokinetics of tobramycin during acute pulmonary exacerbations in the pediatric cystic fibrosis population

摘要

Background Individuals with cystic fibrosis (CF) require higher dosages of aminoglycosides due to an increased volume of distribution (V-d) and clearance. Optimal dosing of aminoglycosides in the CF population is essential as repeated exposure to aminoglycosides during acute pulmonary exacerbations increases risk of nephrotoxicity and ototoxicity. To date, no studies have evaluated whether chronic cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy affects pharmacokinetics of aminoglycoside antibiotics in patients with CF. The objective of this study was to determine if the addition of a CFTR modulator affects elimination rate (K-e) for intravenously administered tobramycin in the pediatric CF population. Methods This retrospective study included patients aged 2 to 18 years with CF receiving chronic therapy with a CFTR modulator. Patients included had an admission both pre- and post-chronic CFTR modulator therapy during which they received therapy with IV tobramycin. Results Thirty-four patients were included in the study. The median time between pre- and post-modulator admissions was 16.5 (13.8) months. Duration of CFTR modulator therapy before post-modulator admission was a median of 8 (10.3) months. There was no significant difference in K-e(hr(-1)) between pre- and post-modulator therapy, 0.41 (0.21) pre and 0.39 (0.09) post (P = .5). V(d)and peak concentration were similar between both groups. There was no difference in nephrotoxicity as defined by the pRIFLE criteria (P = .25). Conclusions The pharmacokinetic parameters of intravenously administered tobramycin during admission for acute pulmonary exacerbation do not appear to change significantly after initiating chronic therapy with a CFTR modulator. Empiric dose adjustments for patients on CFTR modulators are not recommended.