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.