Pharmacokinetics
Midazolam
The mean ± standard deviation (SD) of Cmax and AUC0-t of oral midazolam before repeated administration of carotegrast methyl (day -1) was 30.9 ± 9.8 ng mL-1 and 74.5 ± 21.9 ng h mL-1, respectively. The Cmax and AUC0-t of midazolam after 14-day administration of carotegrast methyl (day 14) was 56.6 ± 14.4 ng mL-1 and 225.1 ± 50.0 ng h mL-1, respectively. The geometric mean ratio of the Cmax and AUC0-t of midazolam on day 14 to those on day -1 was 1.86 (90% CI, 1.64 – 2.11) and 3.07 (90% CI, 2.81 – 3.35), which did not fall within the range of 0.80 – 1.25, suggesting that carotegrast methyl had a pharmacokinetic interaction with oral midazolam. The Cmax and AUC0-t of midazolam 14 days after the end of carotegrast methyl administration (day 28) was 33.7 ± 11.5 ng mL-1 and 83.9 ± 26.1 ng h mL-1, respectively. The geometric mean ratio of the Cmax and AUC0-t of midazolam on day 28 to those on day -1 was 1.08 (90% CI, 0.95 – 1.22) and 1.12 (90% CI, 1.02 – 1.22), respectively, which fell within the range of 0.80 − 1.25.
The AUC0-t of intravenous midazolam before repeated administration of carotegrast methyl (day -1), after the 14-day repeated administration (day 14), and 14days after the end of the repeated administration (day 28) was 48.8 ± 12.1, 73.7 ± 14.5, and 56.0 ± 12.3 ng h mL-1, respectively. The geometric mean ratio of the AUC0-t of intravenous midazolam on day 14 to those on day -1 was 1.53 (90% CI, 1.43 – 1.64), which did not fall within the range of 0.80 – 1.25, suggesting that carotegrast methyl had a pharmacokinetic interaction with intravenous midazolam. The geometric mean ratio of the AUC0-t of intravenous midazolam on day 28 to those on day -1 was 1.16 (90% CI, 1.08 – 1.24).