ABSOLUTE BIOAVAILABILITY AND ABSORPTION CHARACTERISTICS OF AEROSOLIZED TOBRAMYCIN IN ADULTS WITH CYSTIC-FIBROSIS

Administration of antibiotics by the inhalational route has become part of standard protocols for treatment of and prophylaxis for Pseudomonal pneumonias in patients with cystic fibrosis. For tobramycin, however, limited data are available on the aerosol absorption patterns, and no absolute bioavailability data for tobramycin exist. The purpose of this study was to measure the absolute bioavailability and systemic absorption characteristics of tobramycin when administered in high doses by a nebulizer. Multiple serum concentrations of tobramycin were measured after administration of an intravenous dose (mean, 2.9 mg/kg every 6 hours) and after an inhalational dose (5.6 mg/kg over 1 hour). Inhalational doses were superimposed over the ''tail'' of a steady-state intravenous dose to improve the sensitivity of the assay procedure (Abbott-TDX). Absolute bioavailability (F) was determined from AUC ratios normalized for dose. Model-independent pharmacokinetic parameters (volume of distribution [V-ss] and total clearance [CLt]) were determined for each subject. Absorption characteristics (absorption rate constant [Ka] and mean absorption time [MAT]) were assessed after calculation of the cumulative fraction of drug absorbed, amount of bioavailable drug, and percent remaining to be absorbed per unit time using the Loo-Riegelman method. Three men and three women completed the study, and all received concurrent doses of ceftazidime. Mean absolute bioavailability (+/- standard deviation) was 9.13% (+/- 3.82), and the rate of absorption into the systemic circulation was consistent with a zero-order model profile for all subjects. Mean absorption time values reflected a wide degree of subject variability and ranged from approximately 15 to 150 minutes. The authors conclude that there is limited uptake of tobramycin into the systemic circulation when administered by nebulizer aerosol into the lungs even in high doses. Absorption of tobramycin from the alveolar space into the pulmonary vasculature appears to be rate limited, but this may be characteristic for adults with cystic fibrosis. The authors also conclude that high doses of tobramycin administered by aerosolized nebulizer in these patients would contribute little to the risk of toxicity because of the poor systemic uptake of this drug.