Inhibition of leukotriene D₄-induced bronchoconstriction in subjects with asthma: A concentration-effect study of ICI 204,219

The peptide-leukotriene antagonist, ICI 204,219 [4-(5-cyclopentyloxycarbonylamino-lmethylindol-3-ylmethyl)-3-methoxy-n-o- tolylsulfonyl benzamide], was administered 12 hours before an inhaled leukotriene D₄ (LTD₄) challenge during a double-blind, placebo-controlled, randomized, two-period crossover trial. Subjects with mild asthma were randomized into five treatment groups (six subjects each) and received single oral doses of placebo and either 5, 10, 20, 40, or 100 mg of ICI 204,219 on day 1 of each treatment period. ICI 204,219 was tolerated well by all subjects. A progressive dose response was observed for doses of ICI 204,219 from 5 mg through 100 mg. Compared with placebo, ICI 204,219 increased the concentration (PC₂₀FEV₁) and dose of LTD₄ needed to reduce forced expiratory volume in 1 second (FEV₁) by 20%. Mean LTD₄ PC₂₀FEV₁ for groups that received placebo and 10,40, or 100 mg ICI 204,219 increased by tenfold or more (p < 0.05). An association was found between the plasma concentration and protective effect of ICI 204,219 (p < 0.01). ICI 204,219 is the first leukotriene receptor antagonist for which a relationship has been established between drug plasma levels and its protective effect in subjects with asthma.