DISCUSSION
Carotegrast methyl is a moderate time-dependent inhibitor of CYP3A4 in vitro. This phase 1 clinical study in healthy males demonstrated that repeated administration of carotegrast methyl increased exposure to CYP3A4 substrates such as midazolam and atorvastatin, but not to prednisolone, which is used for treating UC.
Carotegrast methyl affected the PK of midazolam, a typical substrate drug susceptible to PK interactions due to inhibition of CYP3A414-16, and increased the AUC0-tof midazolam by 2.7-fold on day 7 and 3.1-fold on day 14, compared to midazolam administration alone (day -1). Based on these results, carotegrast methyl was classified as a moderate CYP3A4 inhibitor according to the guideline.13 Increase in the AUC0-t of intravenous midazolam under coadministration with carotegrast methyl was also observed, but was lower than that with oral midazolam. The lower ratios seen compared to oral midazolam might be due to lack of metabolization by CYP3A4 in the gastrointestinal tract; this means the gastrointestinal CYP3A4 would be mainly involved in midazolam metabolism rather than liver CYP3A4. Based on the in vitro study, carotegrast methyl might increase exposure of a strong CYP3A4 probe substrate such as midazolam 8.3-fold in the blood and 1.5-fold in the gastrointestinal tract. On the other hand, in this study, the exposure of midazolam showed a 3.1-fold increase for oral administration and 1.5-fold increase for intravenous administration, suggesting that the contribution of CYP3A4 in the gastrointestinal tract was roughly double. The increase in exposure for intravenous administration of midazolam was 1.5-fold and no significant AEs were observed. Therefore, there are no major concerns regarding the use of carotegrast methyl in combination with midazolam as a sedative for endoscopy procedures.
The degree of increase in AUC0-t of the interacting drugs with coadministration with carotegrast methyl did not differ significantly between the different times of administration of midazolam (days 7 and 14). Carotegrast methyl inhibitory activity against CYP3A4 appeared to have reached almost steady state 7 days after repeated administration of carotegrast methyl, and evaluation on day 14, as set in this study, seemed reasonable. The carotegrast methyl inhibitory activity disappeared 14 days after the end of administration as was also reported for evacetrapib.30
Carotegrast methyl also affected the PK of atorvastatin, a moderate substrate drug susceptible to PK interactions due to inhibition of CYP3A4,23-25 and increased atorvastatin exposure AUC0-t by 1.8-fold on day 7 and 2.1-fold on day 14, compared to atorvastatin administration alone (day -1). Carotegrast methyl did not affect the PK of prednisolone, which is a drug commonly used to treat UC colitis and known to be metabolized by CYP3A4.20,21,31 The Tmax of atorvastatin and prednisolone was delayed when coadministered with carotegrast methyl compared to the Tmax in the absence of carotegrast methyl administration. No delay in Tmaxwas reported when itraconazole was combined with prednisolone20 or atorvastatin32. No delay in Tmax was observed in combination with oral midazolam in liquid form. These results suggest that the delayed Tmax may be caused not by metabolic inhibition, but by concurrent use with carotegrast methyl, which may affect the disintegration and dissolution of prednisolone and atorvastatin tablets, leading to delayed absorption.
In terms of the administration and dose of the interacting drugs used in this study, the tolerability in combination with carotegrast methyl was considered acceptable. Oral carotegrast methyl 960 mg three time daily for 14 days was also well tolerated.
CONCLUSION
Carotegrast methyl is a moderate inhibitor of CYP3A4 and repeated oral administration increased exposure to CYP3A4 substrates such as midazolam and atorvastatin in humans. However, no increase was observed with prednisolone. The inhibitory effect of carotegrast methyl on CYP3A4 had almost disappeared 14 days after the end of the repeated administration. Combination with carotegrast methyl may enhance the pharmacological activity of certain drugs metabolized by CYP3A4. The AEs observed at the dosages of the interacting drugs used in this study were mild in severity and well tolerated when used in combination with carotegrast methyl.