Inhalation of a dry powder tobramycin PulmoSphere formulation in healthy volunteers.
OBJECTIVE
To evaluate the efficiency and reproducibility of pulmonary delivery of an investigational tobramycin PulmoSphere formulation (PStob) [Inhale Therapeutic Systems; San Carlos, CA] by a passive dry powder inhaler, and to compare serum concentrations and whole-lung deposition with a commercial nebulized tobramycin product (TOBI; Chiron Corporation; Seattle, WA).


METHODS
A five-period, open-label, nonrandomized crossover study.


METHODS
Fourteen healthy volunteers were studied, and 12 completed the study.


METHODS
PStob powder was manufactured using lipid-based PulmoSphere technology, producing highly dispersible porous particles. PStob was radiolabeled with (99m)Tc, and in vitro experiments confirmed it as a valid drug marker. To identify whole-lung distribution via scintigraphy, subjects inhaled contents of a single capsule (72 L/min) containing 25 mg of (99m)Tc-labeled PStob (13.5 mg of tobramycin free base) in periods 1 to 3. In period 4, subjects received (99m)Tc nebulized tobramycin, approximately 2.5 mL of 300 mg/5 mL. Deposition and blood samples were obtained. In period 5, six 25-mg doses of unlabeled PStob (81 mg of tobramycin base) were inhaled and blood samples were collected.


RESULTS
Mean whole-lung deposition of PStob was 34 +/- 6% and nebulized tobramycin was 5 +/- 2%. Peak tobramycin concentration in serum (Cmax) values were 0.6 microg/mL with PStob and 0.28 microg/mL after nebulized tobramycin. Serum area under the curve was 4.4 microg x h/mL vs 2.1 micro g x h/mL for nebulized tobramycin. Median time to Cmax for PStob was comparable to nebulized tobramycin.


CONCLUSIONS
The aerosol doses of PStob (25 mg and 150 mg) were well dispersed and tolerated. Serum drug concentrations matched scintigraphy data and were roughly twice that of the comparator. Intrasubject dose variability for three equivalent periods did not exceed 18% relative SD. PStob Cmax (0.6 microg/mL) was well below the toxic threshold (2 micro g/mL).
Newhouse
Michael T
MT
Inhale Therapeutic Systems Inc., San Carlos, CA 94070, USA.
Hirst
Peter H
PH
Duddu
Sarma P
SP
Walter
Yulia H
YH
Tarara
Thomas E
TE
Clark
Andrew R
AR
Weers
Jeffry G
JG
D000280:Administration, Inhalation; D000328:Adult; D000336:Aerosols; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D008168:Lung / Q000000981:diagnostic imaging*; D008297:Male; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D011208:Powders; D011877:Radionuclide Imaging; D013667:Technetium; D014031:Tobramycin / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000336:Aerosols; D000900:Anti-Bacterial Agents; D011208:Powders; D013667:Technetium; D014031:Tobramycin