PHARMACODYNAMICS AND PHARMACOKINETICS OF BAY-X-7195 AEROSOL, A NEW AND SELECTIVE RECEPTOR ANTAGONIST OF CYSTEINYL-LEUKOTRIENES, IN NORMAL VOLUNTEERS

1 The safety, tolerability and pharmacokinetics of BAY x 7195 aerosol, a new selective receptor antagonist of cysteinyl-leukotrienes, were i nvestigated in healthy male volunteers in two observational studies (1 and 2 mg; n = 5 each) and two double blind, placebo-controlled two wa y crossover studies (4 and 8 mg; n = 6 each) using the commercially av ailable Inhaler Ingelheim M(R). 2 The pharmacodynamic effect was asses sed by testing the ability of BAY x 7195 aerosol to inhibit leukotrien e-D-4 (LTD(4)) induced bronchoconstriction in healthy volunteers. Usin g a double-blind, placebo-controlled three way crossover design, volun teers received 2 and 4 mg of BAY x 7195 by means of a newly developed metered dose dry powder inhaler. Bronchoprovocation with nebulized LTD (4) was performed 20 min and 8 h (n = 6 each) after drug administratio n. Specific airways conductance (SGaw) served to assess the airway's r esponse. 3 BAY x 7195 aerosol was safe and well tolerated. Inhalation of the aerosol had no effect on baseline lung function. Only one volun teer reported cough following the inhalation of the 8 mg dose. 4 The p harmacokinetics of unchanged drug following the administration of BAY x 7195 aerosol were linear in the investigated range of doses and in g eneral very similar to a previously investigated tablet formulation. P lasma-concentration vs time courses followed a two-compartment body mo del. Compared with oral administration of the tablet formulation absor ption tended to be more rapid with the aerosol formulation. 5 Compared with placebo, 2 and 4 mg BAY x 7195 increased the concentration of LT D(4) needed to produce a 35% decrease in SGaw 20 min after drug admini stration by a mean (geometric) of 14.2 and 29.7 fold, respectively. Fo r both doses only three volunteers showed a protective effect against LTD(4) induced bronchoconstriction 8 h after drug administration. Indi vidual shifts in the concentration-response curve ranged between 0.4 a nd 7.2 fold. 6 In conclusion, the present results suggest that BAY x 7 195 aerosol is a safe and potent but short acting receptor antagonist of cysteinyl leukotrienes in man.