Parameter | Geometric mean (CV%) | ||||
100 mg two times per day (n=3) | 200 mg two times per day (n=3) | 400 mg two times per day (n=3) | 600 mg two times per day (n=3) | 800 mg two times per day (n=3) | |
Cycle 1, day 1 | n=3 | n=3 | n=3 | n=3 | n=3 |
AUC0–8 (ngxh/mL) | 3550 (14.4) | 8740 (13.6) | 27,700 (21.4) | 50,400 (7.7) | 14,600 (85.1) |
AUC0–8/dose (ngxh/mL/mg) | 35.5 (14.4) | 43.7 (13.6) | 69.1 (21.4) | 84.0 (7.7) | 18.2 (85.1) |
Cmax (ng/mL) | 806 (9.9) | 2110 (13.6) | 7670 (39.6) | 11,700 (24.6) | 2770 (83.6) |
Cmax/dose (ng/mL/mg) | 8.06 (9.9) | 10.5 (13.6) | 19.2 (39.6) | 19.6 (24.6) | 3.47 (83.6) |
tmax, hours (min, max)* | 1.08 (1.08, 2.12) | 2.10 (2.07, 3.08) | 1.08 (1.07, 1.08) | 1.00 (0.97, 1.07) | 2.08 (2.07, 4.12) |
Cycle 1, day 8 | n=3 | n=3 | n=3 | n=3 | n=3 |
Cpre (ng/mL) | 156 (58.2) | 96.5 (85.0) | 1240 (51.6) | 4410 (54.5) | 5200 (105.4) |
Cpre/dose (ng/mL/mg) | 1.56 (58.2) | 0.482 (85.0) | 3.11 (51.6) | 7.35 (54.5) | 6.50 (105.4) |
Cycle 1, day 15 | n=3 | n=3 | n=3 | n=3 | n=1 |
AUC0–8 (ngxh/mL) | 4790 (25.4) | 7580 (11.5) | 31,500 (28.8) | 59,500 (12.7) | 93,200† |
AUC0–8/dose (ngxh/mL/mg) | 47.9 (25.4) | 37.9 (11.5) | 78.8 (28.8) | 99.2 (12.7) | 116† |
Cmax (ng/mL) | 975 (34.9) | 1720 (20.5) | 6560 (27.4) | 12,100 (2.2) | 21,100† |
Cmax/dose (ng/mL/mg) | 9.75 (34.9) | 8.58 (20.5) | 16.4 (27.4) | 20.2 (2.2) | 26.4† |
tmax, hour (min, max)* | 3.08 (2.12, 4.13) | 2.10 (1.00, 6.08) | 1.08 (0.50, 3.00) | 1.03 (0.93, 2.17) | 2.00† |
Racc(AUC0–8) | 1.35 (11.4) | 0.868 (15.3) | 1.14 (50.1) | 1.18 (9.4) | 4.67† |
Racc(Cmax) | 1.21 (24.8) | 0.815 (7.0) | 0.856 (66.8) | 1.03 (23.0) | 5.26† |
Cpre (ng/mL) | 221 (20.5) | 199 (53.9) | 1630 (45.7) | 3380 (42.4) | 9810† |
Cpre/dose (ng/mL/mg) | 2.21 (20.5) | 0.997 (53.9) | 4.08 (45.7) | 5.63 (42.4) | 12.3† |
Cycle 2, day 1 | n=3 | n=2 | n=3 | n=2 | n=1 |
Cpre (ng/mL) | 128 (67.7) | 83.3, 85.2* | 957 (72.1) | 1910, 2560† | 8560† |
Cpre/dose (ng/mL/mg) | 1.28 (67.7) | 0.417, 0.426* | 2.39 (72.1) | 3.18, 4.27† | 10.7† |
*Descriptive statistics were not calculated since n<3; values presented are individual.
†tmax data are presented as median (min, max).
AUC0–8, area under the drug concentration–time curve from 0 to 8 hours postdose; Cmax, maximum observed concentration; Cpre, predose concentrations; CV%, coefficient of variation (in %); Racc(AUC0–8), accumulation of M4112 AUC0–8; Racc(Cmax), accumulation of M4112 Cmax; tmax, time to Cmax.