INTRODUCTION
Carotegrast methyl (AJM300) is a small-molecule of α4-integrin antagonist which received its first approval in Japan for the treatment of ulcerative colitis (UC).1 Carotegrast methyl is an ester prodrug of carotegrast, which exerts an anti-inflammatory effect by blocking the interaction of α4β1 or α4β7 integrins and their counter-receptors, VCAM-1 and MAd-CAM-1, followed by inhibiting leucocyte extravasation into inflammatory sites.2 In phase 2 and phase 3 clinical trials,3,4 oral administration of carotegrast methyl 960 mg three times daily after meals for 8 – 32 weeks effectively induced a clinical response in patients with moderately active UC who had an inadequate response or intolerance to at least 5-aminosalicylic acid. In these trials, carotegrast methyl was well tolerated and most adverse drug reactions were mild or moderate in severity. Although progressive multifocal leukoencephalopathy is a known fatal adverse drug reaction to natalizumab,5-7 which is a humanized monoclonal antibody having a mechanism of action similar to that of carotegrast methyl, no events related to carotegrast methyl have been reported so far. Carotegrast methyl is currently being used as an induction therapy for patients with moderately active UC.
After a single oral dose of carotegrast methyl, the drug was absorbed and metabolized mainly by carboxylesterase 1 to carotegrast.8 Carotegrast methyl is mainly excreted in the feces, and excretion in urine is very limited in healthy adults.9 The elimination half-lives (t1/2) of carotegrast methyl and carotegrast after a single dose (960 mg) of carotegrast methyl was 15.8 h and 15.6 h, respectively. The plasma drug concentration reached steady state on day 2 after administration of 960 mg three times daily for six days.1
UC is a chronic inflammatory disease affecting the colon, and is a lifelong condition that develops early in life.10-12Patients treated with carotegrast methyl may require concomitant medications related to other underlying conditions. In the preclinical study, carotegrast methyl inhibited human liver microsome CYP3A4 time-dependently, suggesting a risk of drug-drug interactions with carotegrast methyl in humans. Therefore, we planned a clinical study to investigate drug-drug interactions focusing on CYP3A4, using representative substrates in healthy adult males in accordance with the Pharmaceuticals and Medical Devices Agency (PMDA) Guideline on drug interaction for drug development and appropriate provision of information .13
Here, we report the results of the clinical trial that evaluated CYP3A4-mediated drug-drug interactions following repeated doses of carotegrast methyl in healthy adults using midazolam, prednisolone, and atorvastatin as CYP3A4 substrates.