Animal models to assess potential post-inhalation irritant effects associated with inhaled drugs.

Inhaled drugs could be associated with irritation or inflammation of the respiratory tract resulting in local adverse events including bronchospasm and cough, hampering the development of these drugs. Moreover, the common safety respiratory pharmacology studies sometimes fail to unveil these local irritant effects. The aim of this study was to set-up a series of preclinical models able to detect potential cough or bronchospasm effects associated with inhalation of new drug candidates. The model consists of the use of head-out plethysmography, which allows to monitor lung function parameters as well as cough events during and soon after the inhalation of different aerosol formulations of new drugs. To validate the assay, rats or guinea-pigs were exposed to a series of inhaled compounds (AZD9164, CHF6523 and Nemiralisib) given as dry powder that induced drop in FEV1 or cough as adverse event in humans. Bechlomethasone dipropionate (BDP) was used as negative control. Cough events and lung function parameters were recorded during inhalation and for the following 5 or 120 minutes respectively. AZD9164 showed a significant reduction in tidal volume while CHF6523 and Nemiralisib induced a significant increase in cough events during inhalation compared to vehicle, the effects dropped down immediately after the inhalation, demonstrating that it is possible to detect such effects only during inhalation. No effect was observed with BDP. These data demonstrate that it is possible to assess the potential irritant effects associated with inhaled drugs using a head-out plethysmography applied to the inhalation system, thus helping in the selection of molecules devoid of such effects.