INTRODUCTION
Carotegrast methyl (AJM300) is the first orally administrable small-molecule antagonist of α4-integrin to be approved worldwide for the induction therapy of ulcerative colitis.1 In phase 2 and phase 3 clinical trials,2,3 oral administration of carotegrast methyl 960 mg three times daily after meals for 8 – 32 weeks effectively induced a clinical response in moderately active ulcerative colitis patients 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 (PML) is known to be a fatal adverse drug reaction to natalizumab,4-6 which is a humanized monoclonal antibody having a mechanism of action similar to that of carotegrast methyl, no such events related to carotegrast methyl have been reported so far. In order to reduce the risk of PML, the administration period should be no longer than 6 months. If the treatment is repeated, a drug holiday of at least 8 weeks between consecutive administrations is required.7
Carotegrast methyl is an ester prodrug of carotegrast, which is orally absorbed and metabolized mainly by carboxylesterase 1 in the liver rather than in the small intestine to its active metabolite, carotegrast.8 Carotegrast methyl is partly metabolized by cytochrome P450 (CYP) 3A4 to demethylated carotegrast methyl (M-I) and then M-II (Figure 1). Carotegrast methyl is mainly excreted in the feces as carotegrast and its glucuronidate conjugate and excretion in urine is very limited in healthy adults.9
Ulcerative colitis is a chronic inflammatory disease affecting the colon, and is a lifelong condition that develops early in life.10-12 Patients treated with carotegrast methyl may require concomitant medications related to other underlying conditions. Therefore, it is important to evaluate the potential drug-drug interactions of carotegrast methyl. In the previous clinical study, we demonstrated that carotegrast methyl was a moderate inhibitor of CYP3A4 and that 14-day repeated oral administration increased exposure to CYP3A4 substrates such as midazolam and atorvastatin, suggesting that coadministration with carotegrast methyl may enhance the pharmacological activity of the drugs metabolized by CYP3A4. Carotegrast was shown to be a substrate for organic anion transporting polypeptide (OATP)1B1/1B3 in vitro, which is an uptake transporter expressed mainly in the liver.13,14 This suggests that OATP1B1 and OATP1B3 may be involved in the uptake process of carotegrast in the human liver, and OATP1B1/1B3 inhibitors may increase the plasma carotegrast concentration by escaping hepatic metabolism and entering systemic circulation. Here, we report the results of a clinical study to evaluate the effects of rifampicin, a potent OATPs inhibitor, on the pharmacokinetics (PK) and safety of carotegrast methyl in healthy volunteers.