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.