Table 3.

Summary of pharmacokinetic parameters of SAR245409

15 mg twice daily30 mg twice daily50 mg twice daily60 mg twice daily120 mg twice daily70 mg once daily90 mg once daily100 mg once daily
Day 1n3725a107b5196
tmax, h, median (range)1.92 (1.00, 2.00)2.00 (1.00, 3.00)1.03 (0.250, 8.00)2.04 (1.00, 4.00)2.08 (0.583, 3.08)2.00 (2.00, 6.00)3.00 (0.500, 6.08)1.50 (0.500, 4.00)
Cmax, ng/mL, geometric mean, mean (CV%)43.5, 53.5 (62.7)105, 121 (56.6)148, 197 (72.1)142, 235 (92.5)277, 379 (85.5)241, 275 (42.7)302, 432 (70.6)269, 349 (62.8)
AUC0–t, h × ng/mL, geometric mean, mean (CV%)155, 197 (82.2)387, 446 (59.5)556, 818 (86.0)675, 1250 (114.0)1180, 2100 (110.0)1240, 1330 (37.6)2110, 3560 (90.8)1340, 1750 (50.0)
Day 27n24c16d53e314f2
tmax, h, median (range)1.50 (1.00, 2.00)2.50 (1.02, 3.07)1.00 (1.00, 3.00)2.00 (1.00, 6.00)2.00 (1.00, 2.07)2.00 (2.00, 2.00)2.50 (1.00, 24.0)4.00 (2.00, 6.00)
Cmax, ng/mL, geometric mean, mean (CV%)126, 133 (44.0)151, 176 (59.1)319, 407 (63.1)126, 162 (60.6)437, 524 (77.6)410, 434 (39.5)285, 361 (68.3)270, 276 (28.5)
Cmin, ng/mL, geometric mean, mean (CV%)5.40, 10.7 (122.2)4.43, 7.49 (122.3)17.2, 37.9 (146.1)8.40, 12.5 (90.1)33.5, 36.3 (43.3)4.39, 5.71 (70.3)9.43g, 15.9 (160.3)12.8, 14.2 (61.7)
AUC0–t, h × ng/mL, geometric mean, mean (CV%)472, 504 (49.4)490, 616 (87.1)1,400, 1,890 (76.0)601, 813 (60.9)2,210, 2,390 (50.3)1,720, 1,790 (31.0)1,830, 2,530 (79.1)2,360, 2,460 (38.7)
t1/2z, h, geometric mean, mean (CV%)2.96, 3.15 (48.7)4.09, 5.19 (87.8)5.92, 7.53 (75.2)7.52, 8.50 (61.7)5.82, 6.39 (55.3)7.34, 8.43 (54.8)7.10, 9.43 (79.1)6.51, 6.58 (19.8)
AUC0–t day 27/day 1 ratio, geometric mean. mean (CV%)2.03, 2.05 (17.7)0.932, 1.01 (44.2)2.58, 3.62 (88.2)1.03, 1.52 (118.9)2.10, 2.18 (39.1)1.28, 1.29 (20.6)1.10, 1.66 (117.6)3.41, 5.68 (113.2)

NOTE: AUC0–t, the area under the plasma concentration–time curve, integrated from time 0 to end of dosing interval (>9 and ≤14 hours for twice daily; >20 and ≤28 hours for once daily) on day 1 and integrated from time 0 to exactly 12 hours (twice daily) or to exactly 24 hours (once daily) on day 27; Cmax, observed maximum plasma concentration over dosing interval; Cmin, observed minimum plasma concentration over dosing interval; CV, coefficient of variation; t1/2z, terminal phase half-life; tmax, time to reach the maximum plasma concentration.

  • aExcept for AUC0–t (n = 22).

  • bExcept for AUC0–t (n = 6).

  • cExcept for t1/2z (n = 3).

  • dExcept for t1/2z (n = 15), and for AUC0–t day 27/day 1 ratio (n = 14).

  • eExcept for AUC0–t day 27/day 1 ratio (n = 2).

  • fExcept for t1/2z (n = 13).

  • gThe geometric mean value for this parameter could not be calculated using all available data because 2 patients had concentrations below the lower limit of quantitation (set to 0) over the dosing interval. When these 2 patients were excluded, the geometric mean Cmin value was 9.43 ng/mL (n = 12).