DISCUSSION
This 2 x 2 crossover phase 1 clinical study in healthy male adults
demonstrated that coadministration of carotegrast methyl with
rifampicin, a potent OATP1B1/1B3 inhibitor, increased exposure of
carotegrast methyl and carotegrast, the main metabolite of carotegrast
methyl. However, coadministration with rifampicin was shown to be safe
and well tolerated at the dosage evaluated in this study.
Carotegrast methyl is an ester prodrug of carotegrast, which is the main
component of the metabolites in the blood after oral administration. The
geometric mean ratios (90% CI) of the AUC0-t and
Cmax of carotegrast in the presence of rifampicin to
those in the absence of rifampicin were 5.59 (4.60 – 6.79) and 4.78
(3.64 – 6.29), respectively.
Both 90% CIs were outside the
range of PK equivalence of 0.80 – 1.25, suggesting that carotegrast has
a PK interaction with rifampicin. Similarly, the AUC0-tand Cmax of unchanged carotegrast methyl in plasma, and
M-I and M-II increased by coadministration of carotegrast methyl with
rifampicin. The PK profiles of carotegrast methyl and its N-demethyl
form, M-I, and carotegrast and its N-demethyl form, M-II were similar to
each other, and their impact on drug-drug interactions was also
comparable.
Carotegrast
is a substrate for hepatic uptake transporters OATP1B1 and OATP1B3 in
vitro;1 therefore, inhibition of OATP1B1 and OATP1B3
by rifampicin resulted in escape from hepatic metabolism and increased
systemic exposure. Carotegrast methyl may be involved as a substrate of
OATP1B1 and OATP1B3 in the body, since carotegrast methyl itself showed
inhibitory activity in vitro. Furthermore, the increase in carotegrast
exposure may be partly due to the inhibitory activity of P-glycoprotein
(P-gp) because carotegrast was a weak substrate of P-gp in in vitro
study. It is reported that single-dose rifampicin increased the exposure
of both lenvatinib19 and
venetoclax20 by inhibiting P-gp.
The dose of 960 mg of carotegrast methyl used in this clinical study was
the highest dose that has been used in clinical studies of carotegrast
methyl to date,3,8,9,17 and there is currently no
clinical experience of administration conditions that resulted in even
higher plasma concentrations than those achieved with 960 mg of
carotegrast methyl. However, coadministration of carotegrast methyl with
rifampicin in this study could elucidate previously unexplored areas in
terms of systemic exposure and safety. Therefore, in this study, we
adopted a sentinel dosing regimen starting from a small number of cases
(two subjects) in Step 1, and gradually transitioned to Step 2 (four
subjects) and Step 3 (14 subjects) while confirming safety and
evaluating PK at each step. It should be noted that even
coadministration of carotegrast methyl with rifampicin was safe and well
tolerated at the dose of 960 mg even though systemic exposure increased.
All AEs observed in relation to coadministration were mild, and neither
SAEs nor AEs leading to treatment discontinuation were observed. In the
clinical studies of carotegrast methyl in patients with ulcerative
colitis, some patients received OATP1B1/1B3 inhibitors such as
clarithromycin, atorvastatin, telmisartan, and tacrolimus as a
concomitant medication, but there was no tendency for an increase in the
incidence of AEs and adverse drug reactions due to the
coadministration.3 Furthermore, there was no increase
in the incidence of AEs leading to discontinuation of treatment.
However, it should be noted that there are very few examples of
coadministration with an OATP1B1/1B3
inhibitor. Therefore, it is
necessary to collect more information during post-marketing surveillance
on the safety of carotegrast methyl when coadministered with drugs that
inhibit OATP1B1 and OATP1B3.