Table 4 E7449 pharmacokinetic parameters (pharmacokinetic analysis set).

From: First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor

Day –2 (single dose)

Dose

50 mg

100 mg

200 mg

400 mg

600 mg

800 mg

n

3

3

4

4

8

6

Cmax (ng/mL)

265 (99.8)

284 (112)

996 (676)

999 (619)

2250 (1330)

4430 (2470)

tmax (h)

2.00 (0.58, 2.03)

2.05 (1.08, 3.00)

3.10 (1.03, 4.18)

2.04 (1.03, 4.05)

2.12 (0.50, 24.3)

0.79 (0.50, 2.00)

AUC(0–24) (ng·h/mL)

768 (n = 1)

879 (104)

3670 (1170)

4690 (2400)

7930 (4990)

11,300 (3230)

AUC(0-t) (ng·h/mL)

603 (213)

879 (104)

3780 (1180)

4800 (2450)

8120 (4990)

11,500 (3370)

AUC(0-inf) (ng·h/mL)

770 (n = 1)

895 (99.8)

3320 (1790) (n = 2)

4800 (3000) (n = 3)

10,700 (5040) (n = 4)

12,900 (3350) (n = 4)

t1/2 (h)

3.42 (n = 1)

6.35 (3.36)

7.08 (1.16) (n = 2)

8.62 (0.54) (n = 3)

7.17 (2.98) (n = 4)

9.45 (2.42) (n = 4)

CL/F (L/h)

64.9 (n = 1)

113 (12.9)

70.7 (38.3) (n = 2)

104 (50.1) (n = 3)

64.1 (23.8) (n = 4)

64.7 (13.4) (n = 4)

Vz/F (L)

321 (n = 1)

1070 (687)

690 (273) (n = 2)

1320 (689) (n = 3)

741 (496) (n = 4)

864 (230) (n = 4)

Ae (mg)

0.11 (0.06) (n = 2)

0.47 (n = 1)

0.70 (0.60) (n = 3)

2.77 (1.82)

2.90 (0.51)

4.00 (1.73)

fe (%)

0.22 (0.13) (n = 2)

0.47 (n = 1)

0.34 (0.29) (n = 3)

0.69 (0.45)

0.48 (0.09)

0.50 (0.22)

CLR (L/h)

– (n = 0)

0.5 (n = 1)

0.2 (0.15) (n = 3)

0.6 (0.34)

5.0 (13.0)

0.4 (0.12)

Cycle 1, day 15 (multiple once-daily doses), steady state

n

3

3

3

3

6

5

Cmax (ng/mL)

264 (227)

404 (175)

1430 (1080)

1130 (1030)

2230 (1570)

4120 (2160)

tmax (h)

1.00 (0.5, 2.00)

3.00 (1.00, 4.00)

1.00 (1.00, 2.00)

4.00 (0.5, 4.00)

1.14 (0.50, 4.05)

0.50 (0.0, 1.97)

AUC(0–24) (ng·h/mL)

714 (193)

1100 (244)

3690 (2230)

4730 (2730)

7900 (4730)

12,400 (5230)

AUC(0-inf) (ng·h/mL)

634 (n = 1)

1150 (266)

2670 (1510) (n = 2)

3240 (820) (n = 2)

9660 (4550) (n = 4)

12,000 (5910) (n = 4)

t1/2 (h)

9.04 (n = 1)

8.92 (2.50)

9.19 (4.83) (n = 2)

4.16 (1.72) (n = 2)

5.05 (1.76) (n = 4)

6.44 (1.56) (n = 4)

Cav,ss (ng/mL)

29.7 (8.03)

45.8 (10.2)

154 (93.1)

197 (114)

329 (198)

516 (218)

CLss /F (L/h)

73.1 (17.1)

94.2 (22.9)

73.3 (50.4)

103 (50.5)

133 (139)

67.1 (28.2)

Rac

1.19 (n = 1)

1.19 (0.11)

1.22 (0.22) (n = 2)

1.03 (0.04) (n = 2)

1.05 (0.05) (n = 4)

1.09 (0.06) (n = 4)

Ae (mg)

0.19 (0.00) (n = 2)

0.70 (n = 1)

1.11 (0.33)

2.05 (1.09)

2.25 (1.28)

4.70 (2.91)

fe (%)

0.39 (0.01) (n = 2)

0.70 (n = 1)

0.55 (0.17)

0.51 (0.27)

0.38 (0.21)

0.68 (0.47)

CLR (L/h)

0.3 (0.01) (n = 2)

0.5 (n = 1)

0.5 (0.4)

0.4 (0.14)

0.3 (0.12)

0.5 (0.34)

  1. Data are the mean (standard deviation) except for tmax.
  2. For tmax, median (minimum – maximum) is shown.
  3. Ae, amount of drug dose excreted in urine; AUC(0–24), area under the concentration–time curve from time zero (pre-dose) to 24 h post dose; AUC(0-t), area under the concentration–time curve from time zero (pre-dose) to the time of the last quantifiable concentration; AUC(0-inf), area under the concentration–time curve from time zero (pre-dose) extrapolated to infinite time; Cav,ss, average steady-state concentration during multiple-dose administration; Cmax, maximum observed concentration; CL/F, apparent total clearance following oral administration; CLss/F, apparent total clearance at steady state following oral administration; CLR, renal clearance; fe, cumulative fraction of drug dose excreted/recovered in urine; Rac, accumulation ratio; tmax, time at which the highest drug concentration occurs; t1/2, terminal elimination phase half-life; Vz/F, apparent volume of distribution at the terminal phase.
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