Pharmacokinetics and bioavailability of aerosolized tobramycin in cystic fibrosis.
OBJECTIVE
To describe the pharmacokinetics and bioavailability of inhaled tobramycin (TOBI; Chiron Corporation; Seattle, WA), 300-mg dose, delivered by a nebulizer (PARI LC Plus; Pari Respiratory; Richmond, VA) and a compressor (Pulmo-Aide, model 5650D; DeVilbiss Health Care; Somerset, PA) in cystic fibrosis (CF) patients during the pivotal phase III trials.


METHODS
Data from two identical, 24-week, randomized, double-blind, placebo-controlled, parallel-group studies.


METHODS
US sites randomized 258 patients with CF to receive tobramycin, 300 mg twice daily, in three 28-day on/28-day off treatment cycles.


METHODS
Tobramycin sputum concentrations were assessed 10 min after the first and last doses were administered in the 20-week study. Serum tobramycin concentrations were assessed before and 1 h after the first and last doses had been administered. The population estimate of the apparent clearance was used to estimate the bioavailability fraction.


RESULTS
The mean peak sputum concentration was 1,237 microg/g. About 95% of patients achieved sputum concentrations > 25 times the minimum inhibitory concentration of the Pseudomonas aeruginosa isolates. One hour after the dose, the mean serum concentration was 0.95 microg/mL. Tobramycin did not accumulate in the sputum or serum over the course of the study. Pharmacokinetic data were best represented by a two-compartment model with biexponential decay and slope estimates comparable to those following parenteral administration. The estimated systemic bioavailability after aerosol administration was 11.7% of the nominal dose.


CONCLUSIONS
The administration of tobramycin, 300 mg bid, in a 28-day off/28-day on regimen produced low serum tobramycin concentrations, reducing the potential for systemic toxicity. High sputum concentrations ensure efficacious antibiotic levels at the site of the infection. Inhaled tobramycin significantly improved the therapeutic ratio over that of parenteral aminoglycosides.
Nemours Children's Clinic, Division of Pulmonology, Orlando, FL 32806, USA. dgeller@nemours.org
David E
DE
Geller
William H
WH
Pitlick
Pasqua A
PA
Nardella
William G
WG
Tracewell
Bonnie W
BW
Ramsey
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000336:Aerosols; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001682:Biological Availability; D002648:Child; D003550:Cystic Fibrosis / Q000145:classification / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D012720:Severity of Illness Index; D014031:Tobramycin / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014481:United States
D000336:Aerosols; D000900:Anti-Bacterial Agents; D014031:Tobramycin