Table 4.
Pharmacokinetic parameters for riociguat and metabolite M1 in healthy individuals (controls) and patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, following a single oral dose of riociguat 1.0 mg (total population of smokers and nonsmokers)
| Parameter | Child-Pugh A (n = 16) | Child-Pugh B (n = 16) | Control A (n = 16) | Control B (n = 16) |
|---|---|---|---|---|
| Riociguat | ||||
| AUC, μg·h/L | 371 (74) | 459 (62) | 350 (67) | 301 (92) |
| AUCnorm, kg·h/L | 30.9 (75) | 36.6 (65) | 29.1 (67) | 23.9 (94) |
| Cmax, μg/L | 42.7 (37) | 43.3 (39) | 42.7 (23) | 38.7 (30) |
| Cmax,norm, kg/L | 3.56 (33) | 3.45 (26) | 3.55 (20) | 3.07 (23) |
| tmax, hours | 0.750 (0.500–3.00) | 1.25 (0.750–4.00) | 0.875 (0.500–3.00) | 1.50 (0.500–3.00) |
| t1/2, hours | 9.19 (53) | 13.7 (50) | 9.02 (63) | 7.54 (86) |
| CL/F, L/h | 2.70 (74) | 2.18 (62) | 2.86 (67) | 3.32 (92) |
| fu, % | 3.23 (22) | 3.81 (37) | 3.34 (20) | 3.45 (23) |
| AUCu,norm, kg·h/L | 0.999 (82) | 1.39 (92) | 0.972 (65) | 0.825 (93) |
| Cmax,u,norm, kg/L | 0.115 (35) | 0.131 (35) | 0.119 (23) | 0.106 (25) |
| AE,ur, % | 9.52 ± 4.79 | 12.2 ± 8.68 | 11.4 ± 5.26 | 9.69 ± 4.69 |
| CLR, L/h | 0.226 (62) | 0.226 (85) | 0.289 (30) | 0.280 (43) |
| Metabolite M1 | ||||
| AUC, μg·h/L | 289 (52) | 266 (56) | 213 (38) | 222 (35) |
| AUCnorm, kg·h/L | 24.9 (44) | 21.9 (60) | 18.4 (34) | 18.2 (31) |
| Cmax, μg/L | 8.41 (78) | 6.55 (79) | 6.86 (68) | 7.79 (73) |
| Cmax,norm, kg/L | 0.725 (70) | 0.540 (69) | 0.591 (64) | 0.640 (66) |
| tmax, hours | 12.0 (2.00–48.0) | 12.0 (2.00–48.0) | 8.00 (2.00–24.0) | 12.0 (3.00–24.0) |
| t1/2, hours | 19.0 (32) | 22.2 (49) | 15.3 (32) | 15.5 (36) |
| CL/F, L/h | 3.34 (52) | 3.64 (56) | 4.53 (38) | 4.36 (35) |
| fu, % | 2.81 (25) | 3.57 (32) | 2.91 (20) | 3.01 (20) |
| AUCu,norm, kg·h/L | 0.702 (53) | 0.787 (55) | 0.535 (47) | 0.548 (38) |
| Cmax,u,norm, kg/L | 0.0204 (76) | 0.0193 (50) | 0.0172 (72) | 0.0193 (70) |
| AE,ur, % | 13.2 ± 7.42 | 7.29 ± 4.57a | 15.2 ± 8.57 | 14.1 ± 6.68 |
| CLR, L/h | 0.396 (88) | 0.234 (98)a | 0.618 (49) | 0.560 (59) |
Data are geometric means (percentage coefficient of variation) except for tmax, which is expressed as median (range), and AE,ur, which is expressed as arithmetic mean ± standard deviation. AE,ur: amount excreted into urine from time 0 to infinity; AUC: area under the plasma concentration–time curve from time 0 to infinity; AUCnorm: AUC divided by dose of riociguat per kilogram of body weight for total (bound and unbound) riociguat/M1; AUCu,norm: AUC divided by dose of riociguat per kilogram of body weight for unbound riociguat/M1; CL/F: apparent oral clearance for total riociguat/M1; CLR: renal clearance of riociguat/M1; Cmax: maximum concentration in plasma; Cmax,norm: Cmax divided by dose of riociguat per kilogram of body weight for total riociguat/M1; Cmax,u,norm: Cmax divided by dose of riociguat per kilogram of body weight for unbound riociguat/M1; fu: fraction unbound; tmax: time to Cmax of total riociguat/M1; t1/2: terminal elimination half-life for total riociguat/M1.
Data were available from 15 patients.