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 investigated in healthy male volunteers in two observational studies (1 and 2 mg; n = 5 each) and two double blind, placebo-controlled two way crossover studies (4 and 8 mg; n = 6 each) using the commercially available Inhaler Ingelheim M. 2. The pharmacodynamic effect was assessed by testing the ability of BAY x 7195 aerosol to inhibit leukotriene-D4 (LTD4) induced bronchoconstriction in healthy volunteers. Using a double-blind, placebo-controlled three way crossover design, volunteers received 2 and 4 mg of BAY x 7195 by means of a newly developed metered dose dry powder inhaler. Bronchoprovocation with nebulized LTD4 was performed 20 min and 8 h (n = 6 each) after drug administration. Specific airways of conductance (SGaw) served to assess the airway's response. 3. BAY x 7195 aerosol was safe and well tolerated. Inhalation of the aerosol had no effect on baseline lung function. Only one volunteer reported cough following the inhalation of the 8 mg dose. 4. The pharmacokinetics of unchanged drug following the administration of BAY x 7195 aerosol were linear in the investigated range of doses and in general very similar to a previously investigated tablet formulation. Plasma-concentration vs time courses followed a two-compartment body model. Compared with oral administration of the tablet formulation absorption tended to be more rapid with the aerosol formulation. 5. Compared with placebo, 2 and 4 mg BAY x 7195 increased the concentration of LTD4 needed to produce a 35% decrease in SGaw 20 min after drug administration by a mean (geometric) of 14.2 and 29.7 fold, respectively. For both doses only three volunteers showed a protective effect against LTD4 induced bronchoconstriction 8 h after drug administration. Individual shifts in the concentration-response curve ranged between 0.4 and 7.2 fold. 6. In conclusion, the present results suggest that BAY x 7195 aerosol is a safe and potent but short acting receptor antagonist of cysteinyl leukotrienes in man.

RCT Entities:   Population Interventions Outcomes