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Pharmacodynamics and pharmacokinetics of BAY x 7195 aerosol, a new and selective receptor antagonist of cysteinyl‐leukotrienes, in normal volunteers
Author(s) -
WENSING G.,
HEINIG R.,
KUHLMANN J.
Publication year - 1996
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1996.03505.x
Subject(s) - crossover study , pharmacokinetics , inhaler , pharmacology , pharmacodynamics , medicine , placebo , tolerability , bronchodilator , inhalation , aerosol , dry powder inhaler , leukotriene , anesthesia , chemistry , asthma , adverse effect , pathology , alternative medicine , organic chemistry
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‐D 4 (LTD 4 ) 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 LTD 4 was performed 20 min and 8 h ( n =6 each) after drug administration. Specific airways 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 LTD 4 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 LTD 4 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.