Table 3 Pharmacokinetic parameters of zibotentan in subjects with normal renal function and varying degrees of renal impairment, normal hepatic function and varying degrees of hepatic impairment
| Â | Â | Degree of hepatic impairment | Â | Degree of renal impairment | ||||
|---|---|---|---|---|---|---|---|---|
PK parameter | Normal hepatic function (n = 8) | Mild (n = 8) | Moderate (n = 8) | Severe (n = 8) | Normal renal function (n = 18) | Mild (n = 12) | Moderate (n = 9) | Severe (n = 9) |
AUC(0-t) (ng·h/mL)* | 5460 (46.2) | 7560 (65.1) | 7850 (50.3) | 15100 (49.8) | 5560 (36.9) | 6910 (57.5) | 9090 (35.2) | 9640 (37.7) |
AUC (ng·h/mL)* | 5480 (46.0) | 7680 (68.8) | 7940 (50.7) | 15900 (52.9) | 5490 (39.0)$ | 6950 (58.3) | 8710 (3.8)£ | 9750 (38.8) |
Cmax (ng/mL)* | 566 (25.6) | 526 (22.3) | 505 (23.0) | 536 (30.2) | 545 (22.7) | 531 (28.8) | 550 (9.9) | 619 (20.6) |
tmax (h)†| 2 (1-2) | 2 (1-4) | 2 (1-6) | 2 (1-4) | 1 (1-3) | 1 (1-4) | 2 (1-8) | 1 (1-3) |
t1/2 (h)‡ | 9.3 (3.6) | 13.0 (9.4) | 14.6 (6.5) | 24.8 (10.9) | 10.8 (2.7)$ | 11.3 (4.0) | 13.5 (4.3)£ | 13.2 (4.7) |
CL/F (mL/min)‡ | 33.2 (15.6) | 25.0 (12.1) | 23.6 (14.2) | 11.9 (7.3) | 32.7 (14.2)$ | 27.9 (18.9) | 20.1 (6.5)£ | 18.2 (6.5) |
Vss/F (L)‡ | 19.0 (6.1) | 19.8 (3.1) | 21.2 (7.2) | 21.9 (7.1) | 22.6 (7.0)$ | 20.8 (5.8) | 19.3 (2.0)£ | 17.8 (3.4) |
Fu (%)‡ | 22.5 (7.5) | 23.4 (4.0) | 20.2 (4.8) | 29.2 (9.4) | 22.8 (6.2) | 25.4 (6.7) | 26.6 (2.9) | 27.9 (5.3) |
CLR (mL/min)‡ | - | - | - | - | 17.4 (13.9)$ | 10.3 (16.8) | 3.2 (5.6)£ | 2.3 (2.7)£ |
Fe (%)‡ | - | - | - | - | 47.2 (18.0) | 27.1 (19.5) | 12.7 (16.9) | 10.5 (9.0)£ |
Free Cmax (ng/mL)* | 121 (58.7) | 123 (21.9) | 97.3 (32.4) | 149.2 (52.6) | 121 (32.3) | 131 (22.9) | 145 (13.4) | 170 (18.2) |
Free AUC (ng·h/mL)* | 1170 (69.3) | 1800 (54.7) | 1460 (56.5) | 4430 (40.0) | 1230 (39.1)$ | 1720 (60.6) | 2260 (34.5)£ | 2680 (38.9) |
Unbound CL/F (mL/min)‡ | 167 (98.4) | 103 (46.8) | 129 (69.8) | 40 (14.7) | 146 (67.3)$ | 115 (83.8) | 77.4 (24.1)£ | 65.8 (22.3) |