PK parameters and PARP inhibition following single and multiple daily dosing
| Single talazoparib dose, mg | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| PK parameter | 0.025 (n = 3) | 0.05 (n = 3) | 0.1 (n = 3) | 0.2 (n = 3) | 0.4 (n = 3) | 0.6 (n = 6) | 0.9 (n = 6) | 1.0 (n = 5) | 1.1 (n = 7) |
| Tmax, median (min, max), h | 7.92 (1.95, 9.95) | 1.00 (0.80, 1.02) | 1.02 (1.00, 3.98) | 1.03 (1.00, 2.32) | 2.03 (0.75, 2.95) | 0.835 (0.75, 1.95) | 2.00 (1.02, 9.98) | 1.03 (0.73, 2.07) | 1.00 (0.73, 2.05) |
| Cmax, mean (SD), pg/mL | 60.0 (15.9) | 79.7 (7.50) | 214 (50.9) | 788 (369) | 1,830 (699) | 4,100 (1,400) | 6,100 (3,060) | 10,600 (4,220) | 13,200 (3,220) |
| AUC0–24, mean (SD), pg·h/mL | 952 (386) | 1,160 (166) | 3,160 (1,270) | 9,130 (3,540) | 13,500 (5,200) | 37,900 (12,900) | 58,200 (24,300) | 85,100 (29,100) | 91,600 (31,800) |
| AUC0–t, mean (SD), pg·h/mL | 3,600 (1,360) | 5,340 (1,960) | 16,600 (5,320) | 39,300 (11,700) | 43,700 (15,000) | 97,900 (30,000) | 160,000 (66,100) | 182,000 (62,400) | 201,000 (93,400) |
| AUC0-∞, mean (SD), pg·h/mL | 5,330 (1,840) | 8,320 (1,960) | 37,600 (6,620) | 92,700 (48,500) | 60,100 (15,900) | 120,000 (26,000) | 188,000 (85,700) | 200,000 (64,000) | 235,000 (111,000) |
| t1/2, mean (SD), h | 100 (11.9) | 129 (42.6) | 229 (158) | 212 (126) | 102 (27.2) | 58.6 (17.3) | 60.4 (10.9) | 52.9 (13.4) | 71.0 (20.6) |
| CL/F, mean (SD), L/h | 5.17 (2.10) | 6.27 (1.66) | 2.72 (0.532) | 2.61 (1.35) | 6.95 (1.71) | 5.19 (0.99) | 5.49 (2.08) | 5.39 (1.59) | 5.32 (1.64) |
| Vz/F, mean (SD), L | 756 (351) | 1,240 (742) | 839 (487) | 678 (217) | 1,050 (431) | 441 (143) | 468 (169) | 415 (170) | 549 (232) |
| Multiple daily talazoparib dosing, mg/day | |||||||||
| 0.025 (n = 3) | 0.05 (n = 2) | 0.1 (n = 2) | 0.2 (n = 3) | 0.4 (n = 3) | 0.6 (n = 6) | 0.9 (n = 5) | 1.0 (n = 6) | 1.1 (n = 4) | |
| Tmax, median (min, max), h | 1.02 (0.58, 3.98) | 5.43 (0.77, 10.1) | 0.76 (0.75, 0.82) | 1.97 (1.00, 3.02) | 0.98 (0.75, 2.00) | 1.04 (0.73, 5.98) | 1.02 (0.97, 2.07) | 1.02 (0.75, 2.00) | 1.48 (0.98, 2.00) |
| Cmax, mean (SD), pg/mL | 300 (78.8) | 615 (74.2) | 1,880 (332) | 5,620 (3,530) | 6,560 (1,500) | 11,300 (3,230) | 15,400 (1,540) | 21,000 (7,990) | 23,400 (4,810) |
| AUC0-24, mean (SD), pg·h/mL | 3,960 (759) | 9,770 (2,440) | 30,000 (4,490) | 83,100 (49,300) | 67,300 (22,600) | 119,000 (19,900) | 157,000 (24,500) | 202,000 (54,000) | 188,000 (29,200) |
| t1/2, mean (SD), h | 107 (84.2) | 132 (12.3) | 98.2 (4.83) | 50.9 (19.1) | 90.7 (32.7) | 63.7 (12.7) | 71.0 (14.5) | 50.0 (16.6) | 52.8 (23.2) |
| CLss/F, mean (SD), L/h | 6.43 (1.23) | 5.28 (1.32) | 3.37 (0.502) | 3.12 (1.91) | 6.40 (2.07) | 5.15 (0.897) | 5.86 (0.951) | 5.24 (1.39) | 5.96 (0.837) |
| Vz/F, mean (SD), L | 1,070 (971) | 1,020 (345) | 475 (47.8) | 264 (249) | 818 (326) | 477 (136) | 604 (169) | 373 (144) | 472 (254) |
| Cmin, mean (SD), pg/mL | 169 (58.0) | 299 (133) | 1,020 (107) | 2,880 (1,710) | 2,230 (957) | 3,470 (1,050) | 3,180 (802) | 3,720 (1,590) | 2,910(803) |
| PARP activity, % baseline | |||||||||
| 0.025 (n = 3) | 0.05 (n = 3) | 0.1 (n = 3) | 0.2 (n = 3) | 0.4 (n = 3) | 0.6 (n = 4) | 0.9 (n = 4) | 1.0 (n = 4) | 1.1 (n = 2) | |
| PARP activity, mean (SD) | 172 (206) | 141 (52.5) | 102 (98.0) | 14.7 (5.04) | 111 (96.5) | 24.7 (8.19) | 34.7 (27.4) | 21.1 (14.9) | 16.3 (5.63) |
Abbreviations: AUC0–24, AUC from 0 to 24 h; AUC0–∞, AUC from time 0 extrapolated to infinity; AUC0–t, AUC from time 0 to last quantifiable concentration; CLss/F, CL/F at steady state; SD, standard deviation; Tmax, time to Cmax.