Evaluation of the effect of multiple-dose administration of R411, a dual α4β1–α4β7 integrin antagonist on the major CYP isoform activities in healthy volunteers

Abstract

R411 is a dual antagonist of α4β1–α4β7 integrins that targets the inflammatory process in respiratory airways. It has shown good efficacy in animal disease models [1] and is currently under development for the treatment of chronic asthma. Following oral administration, R411 is rapidly and completely biotransformed into its active metabolite, RO0270608, which is mainly eliminated by biliary excretion. R411 has shown acceptable pharmacokinetics and good safety in healthy volunteers [2]. Due to the frequent polytherapy in asthma patients, the potential of drug-drug interactions should be evaluated. Preclinical studies have shown a low potential of cytochrome P450 (CYP) modulation by RO0270608. However, this is not enough to fully assess the interaction potential in humans. An exploratory clinical trial was conducted to evaluate the effect of oral once-daily administration of R411 on the activities of the principal CYP isoforms and N-acetyl transferase (NAT). Twelve healthy male volunteers were enrolled into a crossover open label study after each provided written informed consent. The study was approved by the Ethics Committee and was conducted at Roche clinical pharmacology unit (Strasbourg, France). All subjects were nonsmokers. Genotyping for CYP2D6 and CYP2C19 was done and poor metabolizers were excluded from the trial. Each subject received a single daily oral dose of 300 mg R411 tablet for 8 consecutive days. Three days before and 8 days after first administration of R411, subjects received the multiprobe “Pittsburgh” cocktail [3], consisting of single oral doses of caffeine, chlorzoxazone, mephenytoin, debrisoquine, and dapsone in order to determine the activities of CYP1A2, CYP2E1, CYP2C19, CYP2D6, and CYP3A, respectively. NAT activity was also determined. Phenotyping indices were determined according to published validated procedures [3]. Probe drugs and their metabolites were assayed by validated methods [4–9]. Equivalence testing was used to compare the activity of the enzymes before and after R411 administration using an analysis of variance (ANOVA) model. The 90% confidence interval (CI) for the difference between treatments in the least squares means was obtained and expressed as a percentage of the reference. Eleven subjects completed the study. One was withdrawn due to a serious adverse event, which occurred after receiving the first dose of the cocktail. He had never received R411 and was thus excluded from the final analysis. Fig. 1 shows the phenotyping indices before and after R411 treatment. Statistical analysis indicated that the 90% CI for the ratio of least squares means for all enzyme activities lies within 80–120% boundaries, with the exception of CYP2C19, where the 90% CI was 77.6–118%. These results indicate that R411 does not affect any of the enzyme Y. Hijazi . H. Welker Hoffmann-La Roche Inc., Clinical Pharmacology, Basel, Switzerland