Table 3

Pharmacokinetic parameters

ParameterGeometric 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 1n=3n=3n=3n=3n=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 8n=3n=3n=3n=3n=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 15n=3n=3n=3n=3n=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 1n=3n=2n=3n=2n=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.