SINGLE-DOSE PHARMACOKINETICS, SAFETY AND TOLERABILITY OF MK-0476, A NEW LEUKOTRIENE D-4-RECEPTOR ANTAGONIST, IN HEALTHY-VOLUNTEERS

MK-0476 or sodium 1-(1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl) 3-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cycloproprane) acetate is a novel, potent, and specific LTD(4)-receptor antagonist. The safety, tolerability and plasma drug profiles of single oral doses of MK-0476 (capsules) were evaluated in 18 healthy male volunteers assigned to one of the two parallel 9-subject panels. Under fasting conditions, increasing single doses of 20 to 800 mg were administered in a first part of the study and in a second part, 200 mg MK-0476 was given either as a solution, under fasting conditions, or as capsules, after a standard breakfast. All volunteers completed the study. Side effects, reported by the investigator to be related to study drug, were mild and transient. No laboratory abnormalities were noted. In the evaluated dose range of MK-0476 (20 to 800 mg) the median value of t(max) ranged from 2 to 4 h, while the apparent t1/2 value averaged 4 to 5 h. The median t(max) value of the 200 mg capsule dose was not significantly different from the median t(max) of the 200 mg oral solution dose indicating that neither disintegration nor dissolution is a rate-limiting step for the absorption of MK-0476 from capsules. There was a statistically significant increase in the AUC (geometric mean ratio of fed/fast was 2.52 with 95% confidence interval of 1.25, 5.06) and in C-max (geometric mean ratio of fed/fast was 1.36 with 95% confidence interval of 0.60, 3.04) when MK-0476 was given together with a breakfast, suggesting an increase in bioavailability. We conclude that single oral doses-of MK-0476 (range 20 to 800 mg) appear to be well tolerated and both formulations (capsule and solution) achieve similar plasma concentrations.