Table 4.
Pharmacokinetic parameters of AZD7762 as monotherapy (cycle 0, day 1) and in combination with gemcitabine (cycle 1, day 8)
| AZD7762 dose (mg)/gemcitabine dose (mg/m2) |
||||||||
|---|---|---|---|---|---|---|---|---|
| 6/750 (n = 6) |
6/1,000 (n = 3) |
9/1,000 (n = 3) |
14/1,000 (n = 6) |
21/1,000 (n = 3) |
30/1,000 (n = 7) |
32/1,000 (n = 6) |
40/1,000 (n = 8) |
|
| AZD7762 monotherapy | ||||||||
| tmax (h)a | 0.9 (0.9–1.0) | 1.0 (0.9–1.0) | 1.1 (0.9–1.4) | 1.0 (0.9–1.0) | 1.0 (0.9–1.1) | 0.9 (0.9–0.9) | 1.0 (0.9–1.0) | 0.9 (0.9–1.0) |
| Cmax (μg/l)b | 39.7 (36) | 22.7 (58) | 51.6 (31) | 87.3 (35) | 154 (20) | 291 (41) | 322 (31) | 279 (27) |
| C24h(μg/l)b | 1.42 (43) | NC | 1.30 (23) | 2.81 (55) | 5.52 (11) | 8.85 (47) | 8.61 (104) | 12.40 (38) |
| AUC (μgh/l)b | 109 (81) | 82.3 (135) | 141 (47) | 295 (38) | 497 (18) | 858 (31) | 822 (32) | 1036 (31) |
| AUC0–1 (h μg/l)b | 87.1 (72.5) | 63.4 (129) | 118 (60.0) | 255 (934.4) | 388 (26.2) | 718 (30.0) | 638 (28.0) | 762 (19.6) |
| AUC0–8 (h μg/l)b | 102 (74) | 77.7 (123) | 139 (45) | 287 (37) | 462 (22) | 825 (30) | 805 (29) | 935 (22) |
| t1/2 (h)a | 11.1 (2.5–23.1) | 10.7 (3.5–15.8) | 8.0 (4.1–10.7) | 9.9 (7.6–11.7) | 13.7 (11.9–16.8) | 11.0 (9.3–13.2) | 9.1 (5.5–14.2) | 15.5 (8.3–28.2) |
| CL (L/h)b | 55.0 (81) | 72.9 (135) | 63.9 (47) | 47.4 (38) | 42.3 (18) | 35.0 (31) | 38.9 (32) | 38.6 (31) |
| Vss (1)b | 490 (54) | 747 (21) | 510 (12) | 508 (33) | 652 (41) | 419 (34) | 347 (31) | 653 (26) |
| AZD7762 plus gemcitabine | ||||||||
| tmax (h)a | 0.9 (0.9–1.0) | 0.9 (0.9–0.9) | 0.9 (0.9–0.9) | 1.0 (0.9–1.1) | 0.9 (0.9–0.9) | 0.9 (0.9–1.0) | 1.0 (0.9–1.1) | 1.1 (0.9–1.6) |
| Cmax (μg/1)b | 41.6 (23) | 44.8 (19) | 63.1 (4) | 86.0 (48) | 159 (12) | 270 (26) | 304 (54) | 205 (50) |
| C24h (μg/1)b | 1.52 (24) | 1.15 (20) | 1.56 (40) | 2.64 (90) | 6.85 (25) | 6.67 (48) | 15.10 (NC) | 14.80 (54) |
| AUC (μg h/l)b | 132 (17) | 88.0 (83) | 171 (33) | 271 (62) | 585 (19) | 687 (28) | 830 (25) | 1234 (51) |
| AUC0–t (h μg/l)b | 103 (16) | 76.3 (77) | 155 (28) | 234 (61) | 447 (19) | 560 (23) | 636 (18) | 849 (31) |
| AUC0–48 (h μg/l)b | 123 (15) | 87.1 (80) | 169 (31) | 264 (61) | 538 (19) | 643 (27) | 814 (19) | 1035 (35) |
| t\m=1/2\ (h)a | 13.8 (10.2–17.1) | 6.3 (1.7–10.9) | 7.5 (3.6–9.7) | 8.9 (2.3–12.6) | 14.5 (14.0–15.2) | 13.8 (11.6–17.1) | 7.4 (2.2–12.6) | 18.1 (10.0– 29.7) |
| CL (l/h)b | 45.4 (17) | 68.2 (83) | 52.6 (33) | 51.6 (62) | 35.9 (19) | 43.7 (28) | 38.6 (25) | 32.4 (51) |
| Vss (1)b | 656 (24) | 313 (65) | 388 (25) | 443 (77) | 600 (18) | 568 (23) | 242 (134) | 667 (34) |
a
Mean (range)
b
Gmean CV (%)
tmax time to maximum concentration. Cmax maximum plasma concentration, C24h plasma concentration 24 h after dosing, AUC area under the plasma-concentration time curve from zero to infinity, AUC0–t AUC from zero to time t, AUC0–48 AUC from zero to 48 h, t\m=1/2\ terminal elimination half-life. CL total body clearance. Vss volume of distribution at steady state, NC not calculable