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).