Effect of R411, a dual α4/β1-α4/β7 Integrin antagonist being developed for asthma, on the activities of the major drug metabolizing enzymes after oral administration in healthy subjects

Abstract

R411 is a novel agent under development for chronic treatment of asthma. It is rapidly and completely converted to its active metabolite, RO027-0608. The objective of this study was to assess the effect of oral administration of R411 on the activity of the major drug-metabolizing enzymes: CYP3A, CYP1A2, CYP2D6, CYP2C19, and CYP2E1, using a multi-probe drug cocktail. Twelve healthy male subjects were enrolled in this single-center, one-sequence crossover, open-label study. Each subject received a single daily oral tablet dose of 300 mg R411 for 8 days. Three days before and 8 days after R411 administration subjects received a 5-drug combination consisting of single oral doses of 100 mg caffeine, 250 mg chlorzoxazone, 100 mg mephenytoin, 100 mg dapsone, and 10 mg debrisoquine in order to determine activity of the principal CYP450 enzymes. Serial blood and urine samples were collected to determine the drug's concentration. The ratio of the least square means together with their 90% CI for all enzyme activities lies within 80–115 boundaries except for CYP2C19 where the ratio (90% CI) lies between 75–120 boundaries. These results indicate no clinically relevant interaction between R411 and any of the substrates of the CYP3A, CYP1A2, CYP2D6, CYP2C19, and CYP2E1. In conclusion, the drug was well tolerated with no safety concerns after multiple doses. R411 had no effects on the enzyme activities tested, suggesting a low potential for CYP450 drug-mediated interactions. Clinical Pharmacology & Therapeutics (2004) 75, P79–P79; doi: 10.1016/j.clpt.2003.11.303