Sputum tobramycin concentrations in cystic fibrosis patients with repeated administration of inhaled tobramycin

Abstract

Background: Dosing of tobramycin solution for inhalation (TSI) in cystic fibrosis (CF) patients was based on single-dose pharmacokinetic studies. This investigation was prompted by evidence of possible antibiotic accumulation in respiratory secretions with repeated dosing. The objectives were to evaluate whether tobramycin accumulates in respiratory secretions with repeated inhalation, compare total and biologically active tobramycin concentrations in CF sputum, and evaluate sputum induction for obtaining secretions for drug concentration assay.

Methods: Individuals with CF ≥10 years of age were enrolled at the beginning of a course of TSI, 300 mg twice daily for 28 days. Two study visits were conducted, 1-2 days and 24-28 days after initiation of TSI treatment. Induced sputum and expectorated sputum samples were collected for measurement of trough and peak tobramycin concentrations at each visit. Total tobramycin concentrations were measured by high-pressure liquid chromatography and bioactive concentrations by bioassay.

Results: Twenty participants completed the study. Trough concentrations were similar at visits 1 and 2, as were peak concentrations. Trough bioactive and total tobramycin concentrations were similar (mean ratio 1.2, 95% CI 0.56, 1.87), but peak bioactive concentrations were significantly lower than peak total concentrations (mean ratio 0.33, 95% CI 0.23, 0.44). Sputum induction was well tolerated.

Conclusions: No evidence of significant drug accumulation in respiratory secretions with repeat dosing of TSI was seen. Peak bioactive concentrations, although lower than peak total concentrations, were still generally well within the bactericidal range. Sputum induction as a method for determining airway drug concentrations appears safe and feasible.

FIG. 1.

HPLC trough and peak tobramycin concentrations (μg/g) (A) and bioassay trough and peak tobramycin concentrations (μg/mL) (B) are plotted on a log scale. Open circles connected by solid lines denote values for each participant in Group 1. Solid triangles connected by dashed lines denote values for each participant in Group 2.

FIG. 2.

Comparison of bioassay tobramycin concentrations (μg/mL) on the x-axis and HPLC tobramycin concentrations (μg/g) on the y-axis is plotted on a log scale. Open diamonds denote trough values, and solid diamonds denote peak values. The dotted line represents the line of identity.