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.