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.