Gf. Cooney et al., ABSOLUTE BIOAVAILABILITY AND ABSORPTION CHARACTERISTICS OF AEROSOLIZED TOBRAMYCIN IN ADULTS WITH CYSTIC-FIBROSIS, Journal of clinical pharmacology, 34(3), 1994, pp. 255-259
Administration of antibiotics by the inhalational route has become par
t of standard protocols for treatment of and prophylaxis for Pseudomon
al pneumonias in patients with cystic fibrosis. For tobramycin, howeve
r, 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 ab
sorption characteristics of tobramycin when administered in high doses
by a nebulizer. Multiple serum concentrations of tobramycin were meas
ured after administration of an intravenous dose (mean, 2.9 mg/kg ever
y 6 hours) and after an inhalational dose (5.6 mg/kg over 1 hour). Inh
alational doses were superimposed over the ''tail'' of a steady-state
intravenous dose to improve the sensitivity of the assay procedure (Ab
bott-TDX). Absolute bioavailability (F) was determined from AUC ratios
normalized for dose. Model-independent pharmacokinetic parameters (vo
lume of distribution [V-ss] and total clearance [CLt]) were determined
for each subject. Absorption characteristics (absorption rate constan
t [Ka] and mean absorption time [MAT]) were assessed after calculation
of the cumulative fraction of drug absorbed, amount of bioavailable d
rug, and percent remaining to be absorbed per unit time using the Loo-
Riegelman method. Three men and three women completed the study, and a
ll received concurrent doses of ceftazidime. Mean absolute bioavailabi
lity (+/- standard deviation) was 9.13% (+/- 3.82), and the rate of ab
sorption into the systemic circulation was consistent with a zero-orde
r model profile for all subjects. Mean absorption time values reflecte
d a wide degree of subject variability and ranged from approximately 1
5 to 150 minutes. The authors conclude that there is limited uptake of
tobramycin into the systemic circulation when administered by nebuliz
er 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 fi
brosis. The authors also conclude that high doses of tobramycin admini
stered by aerosolized nebulizer in these patients would contribute lit
tle to the risk of toxicity because of the poor systemic uptake of thi
s drug.