Carotegrast
Carotegrast was the main active metabolite of carotegrast methyl, and its mean ± SD of Cmax and AUC were more than double those of carotegrast methyl (1047.8 ± 846.8 vs 2620.1 ± 1843.0 ng mL-1, 2583.0 ± 1522.9 vs 9849.9 ± 4580.6 ng h mL-1, respectively). The geometric mean (95% CI) Cmax of carotegrast increased approximately 4.8-fold from 2170.1 (1629.8, 2889.4) and 10380.6 (8133.2, 13249.0) ng mL-1 by coadministration of carotegrast methyl with rifampicin (p < 0.0001). Similarly, a 5.6-hold increase was observed in the geometric mean (95% CI) AUC0-t from 9051.3 (7477.7, 10956.1) and 50548.0 (41286.2, 61887.5) ng h mL-1 (p < 0.0001). The median (min – max) Tmax of carotegrast after carotegrast methyl administration without/with rifampicin was 2.0 (1.0 – 4.0) h and 4.0 (2.0 – 4.0) h, respectively, which was statistically significant (p = 0.0020), indicating delayed absorption with coadministration of rifampicin. The geometric mean (95% CI) t1/2 was 6.6 (4.9, 8.8) h and 4.9 (4.2, 5.8) h, respectively, indicating a tendency to decrease with coadministration of rifampicin. The geometric mean (95% CI) MRT0-t was 4.6 (4.1, 5.2) h and 5.2 (4.9, 5.6) h, respectively, indicating an increase with coadministration of rifampicin (p = 0.0164). For the other metabolites, M-I and M-II, the Cmax and AUC0-t similarly increased as a result of the combination with rifampicin. Only the AUC0-t of carotegrast-gluc increased by coadministration with rifampicin and disappearance took longer than the others.
Drug interaction of carotegrast methyl with rifampicin
The geometric mean ratio (90% CI) of the Cmax and AUC0-t of carotegrast methyl with coadministration of carotegrast methyl with rifampicin to that of carotegrast methyl alone was 2.08 (1.54 – 2.80) and 2.02 (1.53 – 2.67), respectively. The geometric mean ratios of the t1/2 and MRT0-t considered as reference parameters were 1.35 (1.12 – 1.63) and 1.05 (0.98 – 1.14), respectively. For the Tmax, Wilcoxon’s signed-rank test did not show a significant difference (p = 0.2847) between carotegrast methyl with/without rifampicin.
The geometric mean ratio (90% CI) of the Cmax and AUC0-t of carotegrast with coadministration of carotegrast methyl with rifampicin to that of carotegrast methyl alone was 4.78 (3.64 – 6.29) and 5.59 (4.60 – 6.79), respectively. The geometric mean ratios (90% CI) of the t1/2 and MRT0-t considered as reference parameters were 0.75 (0.58 – 0.97) and 1.13 (1.04 – 1.22), respectively. The median Tmaxof carotegrast was extended from two to four hours by the coadministration with rifampicin (Wilcoxon signed test, p = 0.0020). Regarding M-I and M-II, the geometric mean ratios (90% CI) of the Cmax after coadministration of carotegrast methyl with rifampicin to that of carotegrast methyl alone were 1.42 (1.15 – 1.75) and 3.57 (2.91 – 4.38), respectively, and those of the AUC0-t were 1.58 (1.30 – 1.92) and 6.05 (5.13 – 7.14), respectively. PK parameters of carotegrast-gluc were used as a reference because they deviated from the standards of incurred sample reanalysis. However, the geometric mean ratios (90% CI) of the AUC0-t of carotegrast-gluc after coadministration of carotegrast methyl with rifampicin to that of carotegrast methyl alone was 1.14 (0.99 – 1.30).