Gemcitabine aerosol: in vitro antitumor activity and deposition imaging for preclinical safety assessment in baboons.
OBJECTIVE
To characterize gemcitabine aerosol, its in vitro activity against lung cancer cells, its deposition, and tolerance in a non-human primate model.


METHODS
In vitro cytotoxicity of nebulized gemcitabine against NCI-H460 and A549 lung cancer cells was tested using a growth inhibition assay and compared with non-nebulized gemcitabine. The (99m)Tc-DTPA-radiolabeled gemcitabine aerosol was characterized by cascade impaction and the gemcitabine mass/(99m)Tc activity relationship was established for further quantitative nuclear imaging. Nine weekly inhalations at a target dose of 1 mg/kg body weight of gemcitabine were performed in three baboons using dynamic scintigraphic acquisitions for continuous monitoring of gemcitabine delivery during inhalation. Gemcitabine plasma concentrations were measured during the first inhalation.


RESULTS
Growth inhibition assays for both NCI-H460 and A549 cells did not differ between nebulized and non-nebulized gemcitabine. Aerosol characterization showed a particle mass median aerodynamic diameter of 3.7+/-0.8 microm and a linear relationship between gemcitabine mass (y) and (99m)Tc activity (x) (y=0.82x - 10(-5), R (2)=0.88). No toxicity was observed after nine weekly inhalations of a mean dose of gemcitabine of 11.1 mg (88% of the target dose) as assessed from scintigraphic data. A dose-dependent peak plasma concentration of gemcitabine (20-74 ng/ml) was observed by the tenth minute of inhalation.


CONCLUSIONS
We have characterized a gemcitabine aerosol suitable for intrathoracic airway deposition and demonstrated that jet nebulization does not alter the cytotoxic properties of the drug. In a primate model, we have developed a scintigraphic procedure for the monitoring of aerosol deposition, and we have demonstrated the safety of nine weekly aerosol administrations of gemcitabine.
Gagnadoux
Frédéric
F
Groupe de pneumologie Faculté de Médecine, INSERM, U618, IFR135, 37032 Tours, France. frgagnadoux@chu-angers.fr
Leblond
Valérie
V
Vecellio
Laurent
L
Hureaux
José
J
Le Pape
Alain
A
Boisdron-Celle
Michèle
M
Montharu
Jérome
J
Majoral
Caroline
C
Fournier
Joseph
J
Urban
Thierry
T
Diot
Patrice
P
Racineux
Jean-Louis
JL
Lemarié
Etienne
E
D000336:Aerosols; D000818:Animals; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D005260:Female; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy*; D023421:Models, Animal; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy*; D010215:Papio; D011877:Radionuclide Imaging; D000093542:Gemcitabine
D000336:Aerosols; D003841:Deoxycytidine; D000093542:Gemcitabine