Table 4.
Pharmacokinetic parameters of selumetinib following dosing alone and in combination with either docetaxel or dacarbazine
| Geometric mean (% co-efficient of variation) [n evaluable] | ||||||||
|---|---|---|---|---|---|---|---|---|
| Selumetinib + docetaxel | Selumetinib + dacarbazine | |||||||
| Parameter | Dosed alone | Dosed in combination | Dosed alone | Dosed in combination | ||||
| Selumetinib 50 mg (N = 7) | Selumetinib 75 mg (N = 19) | Selumetinib 50 mg (N = 7) | Selumetinib 75 mg (N = 16) | Selumetinib 50 mg (N = 7) | Selumetinib 75 mg (N = 18) | Selumetinib 50 mg (N = 7) | Selumetinib 75 mg (N = 15) | |
| Selumetinib | ||||||||
| Cmax, ng/mL | 382.5 (114.50) | 1165 (62.27) | 576.6 (41.39) | 1215 (70.09) [13] | 933.5 (43.38) | 1537 (45.53) | 692.7 (56.34) | 1343 (74.40) |
| Tmax, ha | 4.0 (1.0–12.0) | 1.0 (1.0–2.0) | 1.53 (0.5–4.0) | 1.5 (0.5–4.0) [13] | 1.0 (1.0–3.0) | 1.0 (0.5–4.0) | 1.0 (0.5–1.5) | 1.5 (1.0–4.0) |
| AUC(0–8), ng•h/mL | 1144 (52.30) | 2735 (43.05) | 1788 (25.59) | 3788 (57.53) [13] | 2351 (23.14) | 3784 (31.17) | 2460 (44.05) | 4544 (45.42) |
| AUC(0–12), ng•h/mL | 1479 (45.02) | 2999 (42.33) | 2056 (30.40) [5] | 5239 (31.04) [9] | 2652 (22.38) | 4210 (31.55) | 2822 (42.48) | 5317 (43.00) |
| N-desmethyl selumetinib | ||||||||
| Cmax, ng/mL | 31.79 (60.02) | 69.63 (49.65) | 29.41 (175.6) | 40.91 (52.07) [13] | 46.99 (77.29) | 71.21 (69.68) | 14.89 (161.60) | 24.94 (96.48) |
| Tmax, ha | 4.0 (1.0–12.0) | 1.25 (1.0–4.0) | 2.0 (1.0–4.0) | 1.5 (0.5–4.0) [13] | 1.0 (1.0–2.0) | 1.5 (1.0–4.0) | 1.5 (0.5–2.0) | 2.0 (1.0–4.0) |
| AUC(0–8), ng•h/mL | 120.0 (33.99) [6] | 209.4 (37.13) | 170.8 (49.61) [5] | 150.3 (35.51) [13] | 163.8 (70.89) | 212.8 (48.59) | 102.2 (94.56) [5] | 101.5 (72.76) |
| AUC(0–12), ng•h/mL | 151.2 (37.44) [6] | 236.5 (36.06) | 258.5 (42.52) [3] | 172.7 (38.09) [10] | 196.0 (70.11) | 261.3 (40.61) [17] | 277.9 (2.08) [2] | 146.4 (58.26) [12] |
| Docetaxel | ||||||||
| Cmax, ng/mL | 2826 (44.32) | 2109 (83.65) [15] | 2789 (16.66) | 2623 (24.33) [13] | ||||
| Tmax, ha | 1.0 (0.5–1.0) | 0.5 (0.5–1.5) [15] | 0.5 (0.5–1.0) | 1.0 (0.5–1.5) [13] | ||||
| AUC(0–8), ng•h/mL | 3396 (48.98) | 2445 (58.67) [15] | 2978 (7.75) | 2834 (22.27) [13] | ||||
| AUC(0–12), ng•h/mL | 3493 (49.31) | 2533 (55.74) [15] | 3049 (8.90) [6] | 2871 (25.19) [9] | ||||
| Dacarbazine | ||||||||
| Cmax, ng/mL | 29.43 (49.76) | 30.17 (20.38) [16] | 28.86 (34.66) | 30.60 (17.87) [18] | ||||
| Tmax, ha | 1.0 (1.0–1.5) | 1.0 (1.0–1.5) | 1.0 (1.0–1.0) | 1.0 (1.0–1.5) | ||||
| AUC(0–8), ng•h/mL | 95.92 (39.61) [6] | 73.73 (22.24) [15] | 83.20 (45.68) | 78.82 (24.23) [18] | ||||
| AUC(0–12), ng•h/mL | 144.9 (58.46) [4] | 101.5 (23.28) [9] | 132.6 (62.18) [4] | 107.3 (25.27) [15] | ||||
| AIC | ||||||||
| Cmax, ng/mL | 5.151 (28.12) [6] | 4.431 (48.12) [16] | 3.570 (122.10) [6] | 3.298 (38.25) [18] | ||||
| Tmax, ha | 1.5 (1.0–1.5) | 1.5 (1.0–3.0) | 1.5 (1.5–3.0) | 1.5 (1.5–3.0) | ||||
| AUC(0–8), ng•h/mL | 21.54 (28.01) [5] | 17.58 (46.87) [15] | 15.05 (108.10) [6] | 13.29 (38.39) [18] | ||||
| AUC(0–12), ng•h/mL | 28.31 (19.91) [5] | 22.32 (43.91) [7] | 21.40 (90.82) [6] | 19.38 (28.28) [11] | ||||
Docetaxel, 75 mg/m2; dacarbazine, 1000 mg/m2
aMedian value and range
AIC, 5-aminoimidazole-4-carboxamide (main metabolite of dacarbazine); AUC(0–8), area under the concentration-time curve from 0 to 8 h; AUC(0–12), area under the concentration-time curve from 0 to 12 h; Cmax, maximum plasma concentration; Tmax, Time to reach maximum plasma concentration