POTENT LEUKOTRIENE-D(4) RECEPTOR ANTAGONIST ICI-204,219 GIVEN BY THE INHALED ROUTE INHIBITS THE EARLY BUT NOT THE LATE-PHASE OF ALLERGEN-INDUCED BRONCHOCONSTRICTION

ICI 204,219 is a potent and specific leukotriene D4 receptor antagonist that blocks both the early and late responses to allergen challenge in humans when given orally at a dose of 40 mg. Here we report our findings with an inhaled formulation of ICI 204,219 against allergen-induced bronchoconstriction. A group of 10 atopic subjects (mean age 25.6 +/- 4.2; 6 females; FEV1 > 90% of predicted; on inhaled beta2-agonists only) were studied on 2 separate days 2 to 3 wk apart. In a randomized placebo-controlled trial they inhaled eight puffs of a standard metered dose inhaler containing either ICI 204,219 (200 mug/puff, total dose 1,600 gg) or propellant alone. They underwent bronchial allergen challenge 30 min later using a single concentration of allergen previously shown to lower the FEV1 by greater-than-or-equal-to 15%. FEV1 was monitored hourly for 10 h, and urine was collected for LTE4 determination. Inhalation of ICI 204,219 was well tolerated, with no adverse clinical or biochemical effects. There was no significant effect of ICI 204,219 inhalation on basal airway caliber (change in FEV1 30 min after inhalation was -149 +/- 67 ml after placebo versus 3 +/- 38 ml after ICI 204,219; p = 0.08). The early response to allergen was significantly inhibited by ICI 204,219 (the maximum fall in FEV1 was -21.2 +/- 6.1% after ICI 204,219 compared with -38.8 +/- 6.5% on placebo; p = 0.007). There was no statistically significant effect on the late response, however (the maximum fall during the late phase was -27.6 +/- 5.6% after ICI 204,219 and -36.3 +/- 4.9% after placebo, p = 0.17). ICI 204,219 was detectable at low levels in plasma samples taken at both 30 min and 6 h after inhalation, but there was no significant correlation of the 30-min plasma levels and percentage inhibition of the area under the FEV1-time curve for the early phase 0 to 2 h, AUC0-2h, (S = -0.14, p = 0.59). Urinary LTE4 in the 4-h collection after allergen did not differ between placebo and ICI 204,219 treatments (p = 0.31). Correlation of urinary LTE4 and percentage inhibition of AUC0-2h was not statistically significant (S = 0.34, p = 0.19). In two studies we conducted, the effects of ICI 204,219 differed significantly with the routine of administration. It is uncertain whether this is wholly explained by differences in either the amount of drug reaching the LTD4 receptors in the lung or the duration that effective blocking concentrations of ICI 204,219 are present at these receptors after the different formulations.