Table 3.
Pharmacokinetic parameters for riociguat and metabolite M1 in healthy individuals and patients with mild, moderate, or severe renal impairment, following a single oral dose of riociguat 1.0 mg in the mixed population of smokers and nonsmokers
| Parameter | Normal (CLCR > 80 mL/min) |
Mild (CLCR = 50–80 mL/min) |
Moderate (CLCR = 30–49 mL/min) |
Severe (CLCR < 30 mL/min)a |
|---|---|---|---|---|
| Patients, no. | 16 | 15 | 16 | 16 |
| Riociguat | ||||
| AUC, μg·h/L | 246 (51) | 375 (111) | 499 (110) | 523 (70)b |
| AUCnorm, kg·h/L | 20.6 (56) | 29.4 (126) | 42.1 (109) | 29.7 (102) |
| Cmax, μg/L | 36.6 (17) | 44.2 (21) | 42.0 (32) | 40.6 (38)b |
| Cmax, norm, kg/L | 3.07 (17) | 3.48 (25) | 3.54 (30) | 2.97 (40) |
| tmax, hours | 1.00 (0.500–2.00) | 1.00 (0.500–3.00) | 1.00 (0.500–3.00) | 1.00 (0.500–4.00) |
| t1/2, hours | 6.19 (50) | 10.1 (116) | 11.4 (103) | 9.52 (75) |
| CL/F, L/h | 4.07 (51) | 2.67 (111) | 2.00 (110) | 2.61 (95) |
| fu, % | 3.40 (18) | 3.10 (21) | 3.62 (27) | 4.11 (26) |
| AUCu, norm, kg·h/L | 0.702 (53) | 0.912 (123) | 1.53 (129) | 1.22 (107) |
| Cmax, u, norm, kg/L | 0.104 (25) | 0.108 (34) | 0.128 (37) | 0.122 (37) |
| AE, ur, % | 8.73 ± 4.60 | 10.8 ± 7.17c | 6.21 ± 4.01 | 4.04 ± 2.93d |
| CLR, L/h | 0.306 (40) | 0.207 (35)c | 0.0995 (71) | 0.0564 (92)d |
| Metabolite M1 | ||||
| AUC, μg·h/L | 257 (22) | 278 (42) | 418 (44) | 547 (62)b |
| AUCnorm, kg·h/L | 22.3 (20) | 22.6 (40) | 36.5 (40) | 39.0 (50) |
| Cmax, μg/L | 9.85 (48) | 8.01 (94) | 7.94 (55) | 8.73 (52)b |
| Cmax, norm, kg/L | 0.855 (44) | 0.651 (84) | 0.694 (51) | 0.739 (51) |
| tmax, hours | 4.00 (4.00–24.0) | 10.0 (3.00–24.1) | 24.0 (4.00–48.0) | 20.0 (2.00–24.1) |
| t1/2, hours | 13.9 (27) | 22.6 (54) | 31.0 (54) | 30.3 (79) |
| CL/F, L/h | 3.76 (22) | 3.47 (42) | 2.32 (44) | 1.99 (55) |
| fu, % | 2.90 (14) | 2.69 (18) | 3.20 (23) | 3.86 (30) |
| AUCu, norm, kg·h/L | 0.646 (23) | 0.611 (41) | 1.17 (39) | 1.51 (53) |
| Cmax, u, norm, kg/L | 0.0248 (49) | 0.0175 (91) | 0.0222 (44) | 0.0286 (52) |
| AE, ur, % | 19.0 ± 6.85 | 11.5 ± 6.85 | 7.38 ± 3.60d | 4.00 ± 3.40e |
| CLR, L/h | 0.698 (53) | 0.363 (73) | 0.189 (74)d | 0.0645 (69)e |
Values are geometric means (percentage coefficient of variation), except for the number of patients; 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 body weight for total riociguat/M1; AUCu, norm: AUC divided by dose of riociguat per kilogram body weight for unbound riociguat/M1; CLCR: creatinine clearance; 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 body weight for total riociguat/M1; Cmax, u, norm, Cmax divided by dose of riociguat per kilogram 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.
In study I, individuals with severe renal impairment received riociguat 0.5 mg, and therefore pharmacokinetic concentrations recorded for these individuals were normalized to a 1.0-mg dose before analysis; all other participants in both studies received riociguat 1.0 mg.
AUC and Cmax values shown for individuals with severe renal impairment are taken from study II (n = 8), in which individuals with severe renal impairment received riociguat 1.0 mg.
Data available from 14 patients.
Data available from 11 patients.
Data available from 8 patients.