Table 3.
Pharmacokinetic data, cediranib pharmacokinetic data following multiple doses (cycle 2, day 1) and chemotherapy pharmacokinetic data alone (cycle 1, day 1), and in combination (cycle 2, day 1) with cediranib
| Cediranib pharmacokinetic data following multiple doses (cycle 2, day 1) | |||||
|---|---|---|---|---|---|
| Cediranib dose (mg) | n | Multiple-dose pharmacokinetic parameters | |||
| Css,max (ng/mL)a | tmax (h)b | AUCss (ng/mL•h)a | |||
| Arm 1 | 20 | 5 | 65.3 (86.2) | 4.0 (2.0, 6.0) | 986 (98.8) |
| Arm 2 | 30 | 8 | 62.5 (53.3) | 5.0 (0.5, 23.0) | 1099 (59.2) |
| Arm 3A | 20 | 5 | 76.0 (57.6) | 2.1 (2.0, 5.9) | 1014 (54.8) |
| Arm 3B | 20 | 3 | 50.9 (126) | 4.0 (2.0, 4.3) | 668 (124) |
| Arm 4 | 30 | 4 | 74.9 (31.6) | 4.0 (2.0, 4.0) | 1206 (35.3) |
| Trial 2171IL0001 (single-agent cediranib) | 20 | 11 | 66.6 (52.9) | 3.0 (2.0, 6.4) | 774 (51.6) |
| 30 | 12 | 69.6 (49.5) | 2.1 (1.0, 4.0) | 741 (48.7) | |
| Chemotherapy pharmacokinetic data alone (cycle 1, day 1) and in combination (cycle 2, day 1) with cediranib | ||||||
|---|---|---|---|---|---|---|
| Treatment period | Cediranib dose (mg) | Multiple-dose pharmacokinetic parameters | ||||
| Cmax | AUC | |||||
| n | (ng/mL)a | n | (ng/mL•h)a | |||
| Arm 1 | Oxaliplatin alonec | 20/30 | 13 | 3300 (17.9) | 13 | 71400 (28.2)d |
| Oxaliplatin combination | 20/30 | 9 | 3760 (26.0) | 9 | 87000 (23.6)d | |
| 5-FU alone | 20/30 | 13 | 544 (72.9) | NA | NA | |
| 5-FU combination | 20/30 | 8 | 825 (86.5) | NA | NA | |
| Arm 2 | Docetaxel alone | 30/45 | 11 | 2760 (32.0) | 11 | 3770 (37.3) |
| Docetaxel combination | 30/45 | 9 | 3230 (42.0) | 8 | 4460 (44.7) | |
| Arm 3A | Irinotecan alone | 20/30/45 | 16 | 3290 (21.1) | 16 | 20400 (29.2) |
| Irinotecan combination | 20/30/45 | 11 | 3910 (35.2) | 11 | 22800 (32.3) | |
| SN38 alone | 20/30/45 | 16 | 35.4 (50.1) | 9 | 595 (53.5) | |
| SN38 combination | 20/30/45 | 11 | 38.7 (38.9) | 6 | 711 (25.0) | |
| Arm 3B | Irinotecan alone | 20 | 5 | 3040 (18.3) | 5 | 20300 (29.0) |
| Irinotecan combination | 20 | 4 | 3790 (23.7) | 4 | 27700 (44.9) | |
| SN38 alone | 20 | 5 | 29.1 (21.0) | 3 | 482 (22.3) | |
| SN38 combination | 20 | 4 | 35.1 (40.0) | 4 | 583 (54.3) | |
| Arm 4 | Pemetrexed alone | 30/45 | 7 | 180 (14.2)e | 10 | 295 (37.7)e |
| Pemetrexed combination | 30/45 | 6 | 182 (44.3)e | 7 | 264 (21.8)e | |
AUC, area under the plasma concentration-time curve; AUCSS, area under the plasma concentration-time curve at steady state; Cmax, maximum plasma concentration; Cssmax, maximum steady-state drug concentration during dosing interval; tmax, time to reach peak or maximum concentration following drug administration
Values represent the geometric mean and CV% in parentheses;
values represent the median value and the range in parentheses
Oxaliplatin was quantified as total platinum;
for oxaliplatin, due to the prolonged terminal phase half-life of platinum, only the area under the curve from zero to the last quantifiable concentration could be accurately estimated;
units for pemetrexed Cmax are u.g/mL and for AUC u.g.h/mL
Arm 1: cediranib+mFOLFOX6; arm 2: cediranib+docetaxel; arm 3A: cediranib+irinotecan; arm 3B: cediranib + irinotecan and cetuximab; arm 4: cediranib+pemetrexed