Gemcitabine aerosol: in vitro antitumor activity and deposition imaging for preclinical safety assessment in baboons.

<bold>Aim: </bold>To characterize gemcitabine aerosol, its in vitro activity against lung cancer cells, its deposition, and tolerance in a non-human primate model. <bold>Methods: </bold>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. <bold>Results: </bold>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. <bold>Conclusions: </bold>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. [ABSTRACT FROM AUTHOR]