Table 5.
Pharmacokinetic parameters (subjects with paired observations only) at sunitinib 37.5 mg/day plus paclitaxel 175 mg/m2 and carboplatin 6 AUC mg•min/mL
| Alone Mean (%CV) [median] | Combination Mean (%CV) [median] | Geometric mean ratio (combination/alone) | |
|---|---|---|---|
| Schedule 2/1 (n = 4) | |||
| Sunitinib | |||
| Tmax (h)a | 6.0 (4.0–8.0) | 16.0 (6.0–24.0) | N/A |
| Cmax (ng/mL) | 19.1 (23) [20.0] | 28.4 (51) [26.1] | 1.37 |
| AUC0–24 (ng·h/mL) | 332 (27) [342] | 501 (42) [503] | 1.44 |
| SU12662 | |||
| Tmax (h)a | 4.0 (2.0–6.0) | 24.0 (4.0–24.0) | N/A |
| Cmax (ng/mL) | 3.11 (45) [2.99] | 6.61 (68) [5.51] | 1.93 |
| AUC0–24 (ng·h/mL) | 54.1 (48) [52.9] | 96.5 (61) [86.0] | 1.68 |
| Total drug | |||
| Tmax (h) | 6.0 (4.0–8.0) | 15.0 (4.0–24.0) | N/A |
| Cmax (ng/mL) | 22.1 (23) [23.9] | 33.2 (52) [30.6] | 1.38 |
| AUC0–24 (ng·h/mL) | 386 (29) [408] | 597 (44) [607] | 1.48 |
| Paclitaxel | |||
| Tmax (h)a | 3.0 (3.0–3.0) | 3.0 (3.0–3.0) | N/A |
| Cmax (μg/mL) | 4.45 (23) [4.58] | 5.00 (27) [5.49] | 1.11 |
| AUC∞ (μg·h/mL) | 15.5 (17) [16.3] | 16.8 (22) [18.02] | 1.08 |
| Clearance (L/h) | 21.1 (33) [18.4] | 19.8 (41) [16.2] | 0.92 |
| t1/2 (h) | 8.80 (15) [8.36] | 8.23 (17) [8.54] | N/A |
| Total platinum | |||
| Tmax (h)a | 3.5 (3.5–4.0) | 3.5 (3.5–3.5) | N/A |
| Cmax (μg/mL) | 20.6 (29) [19.2] | 22.6 (20) [21.2] | 1.11 |
| AUC0–24 (μg·h/mL) | 65.1 (23) [60.4] | 60.3 (10) [60.3] | 0.94 |
| Free platinum | |||
| Tmax (h)a | 3.5 (3.5–4.0) | 3.5 (3.5–3.5) | N/A |
| Cmax (μg/mL) | 25.2 (37) [24.9] | 21.3 (9) [20.7] | 0.89 |
| AUC∞ (μg·h/mL) | 50.7 (25) [49.5] | 43.0 (6) [42.8] | 0.87 |
| Clearance (L/h) | 13.3 (39) [11.2] | 13.2 (22) [12.4] | 1.02 |
| t1/2 (h) | 4.72 (24) [4.89] | 5.27 (4) [5.27] | N/A |
| CDD schedule (n = 5) | |||
| Sunitinib | |||
| Tmax (h)a | 8.0 (6.0–10.0) | 6.0 (4.0–10.0) | N/A |
| Cmax (ng/mL) | 42.1 (12) [43.7] | 47.0 (15) [44.4] | 1.11 |
| AUC0–24 (ng·h/mL) | 874 (13) [918] | 983 (18) [897] | 1.12 |
| SU12662 | |||
| Tmax (h)a | 8.0 (4.0–10.0) | 6.0 (4.0–10.0) | N/A |
| Cmax (ng/mL) | 13.4 (39) [15.7] | 19.2 (39) [19.8] | 1.44 |
| AUC0–24 (ng·h/mL) | 279 (39) [326] | 395 (37) [430] | 1.43 |
| Total drug | |||
| Tmax (h)a | 8.0 (6.0–10.0) | 6.0 (4.0–10.0) | N/A |
| Cmax (ng/mL) | 55.3 (14) [50.9] | 65.2 (17) [68.3] | 1.17 |
| AUC0–24 (ng·h/mL) | 1,153 (14) [1,115] | 1,379 (15) [1,351] | 1.19 |
| Paclitaxel | |||
| Tmax (h)a | 3.0 (2.0–3.0) | 3.0 (3.0–3.0) | N/A |
| Cmax (μg/mL) | 3.96 (40) [3.62] | 5.24 (50) [4.92] | 1.28 |
| AUC∞ (μg·h/mL) | 14.3 (31) [13.2] | 15.9 (33) [13.6] | 1.11 |
| Clearance (L/h) | 26.5 (34) [29.8] | 23.6 (32) [27.4] | 0.89 |
| t1/2 (h) | 8.89 (14) [8.69] | 7.84 (29) [6.90] | N/A |
| Total platinum | |||
| Tmax (h)a | 3.5 (3.5–4.0) | 3.5 (3.5–4.0) | N/A |
| Cmax (μg/mL) | 23.1 (20) [24.5] | 22.8 (13) [24.7] | 1.00 |
| AUC0–24 (μg·h/mL) | 67.6 (7) [65.5] | 60.6 (11) [64.0] | 0.89 |
| Free platinum | |||
| Tmax (h)a | 4.0 (3.5–4.0) | 3.5 (3.5–4.0) | N/A |
| Cmax (μg/mL) | 20.7 (15) [19.3] | 22.0 (16) [22.5] | 1.06 |
| AUC∞ (μg·h/mL) | 48.3 (9) [49.2] | 43.1 (9) [42.4] | 0.89 |
| Clearance (L/h) | 17.1 (26) [16.5] | 18.9 (22) [21.1] | 1.11 |
| t1/2 (h) | 5.18 (6) [5.09] | 4.16 (26) [4.80] | N/A |
Total drug sunitinib + SU12662; Cmax maximum plasma concentration; t1/2 terminal phase half-life; AUC area under the plasma concentration–time profile for time zero to infinity (AUC∞) or 24 h (AUC0–24); CV coefficient of variation; N/A not applicable; CDD continuous daily dosing
a
Tmax = time for Cmax; median (min, max)