Table S1.
Pharmacokinetic parameters for riociguat and metabolite M1 in nonsmoking healthy individuals and patients with mild, moderate, or severe renal impairment, following a single oral dose of riociguat 1.0 mg
| 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. | 14 | 12 | 12 | 14 |
| Riociguat | ||||
| AUC, μg·h/L | 283 (32.3) | 466 (73.2) | 691 (80.7) | 523 (70)b |
| AUCnorm, kg·h/L | 24.0 (34.9) | 36.7 (79.8) | 57.4 (83.9) | 37.0 (66.6) |
| Cmax, μg/L | 37.7 (16.3) | 46.0 (21.1) | 42.9 (37.0) | 40.6 (38)b |
| Cmax, norm, kg/L | 3.20 (13.5) | 3.62 (24.4) | 3.57 (34.3) | 3.13 (29.2) |
| tmax, hours | 1.00 (0.500–2.00) | 1.00 (0.750–3.00) | 1.25 (0.750–3.00) | 1.00 (0.500–4.00) |
| t1/2, hours | 7.00 (36.9) | 12.2 (72.6) | 15.8 (71.8) | 11.1 (60.5) |
| CL/F, L/h | 3.54 (32.3) | 2.15 (73.2) | 1.45 (80.7) | 2.13 (65.0) |
| fu, % | 3.39 (19.4) | 3.14 (22.5) | 4.00 (22.8) | 4.21 (27.0) |
| AUCu, norm, kg·h/L | 0.813 (32.6) | 1.15 (80.6) | 2.30 (80.4) | 1.56 (63.7) |
| Cmax, u, norm, kg/L | 0.108 (24.5) | 0.114 (36.4) | 0.143 (35.5) | 0.132 (22.6) |
| AE, ur, % | 9.63 ± 4.19 | 11.4 ± 7.28 | 7.65 ± 3.55 | 4.04 ± 2.93c |
| CLR, L/h | 0.312 (42.6) | 0.208 (37.8) | 0.105 (55.2) | 0.0564 (92.1)c |
| Metabolite M1 | ||||
| AUC, μg·h/L | 256 (23.7) | 285 (43.8) | 407 (50.2) | 547 (62)b |
| AUCnorm, kg·h/L | 22.5 (21.5) | 23.2 (44.0) | 35.0 (44.8) | 40.9 (48.9) |
| Cmax, μg/L | 8.92 (40.8) | 7.09 (74.4) | 6.85 (55.0) | 8.73 (52)b |
| Cmax, norm, kg/L | 0.783 (37.8) | 0.577 (69.7) | 0.589 (46.0) | 0.679 (45.5) |
| tmax, hours | 8.00 (4.00–24.0) | 11.0 (3.00–24.1) | 24.0 (4.00–48.0) | 24.0 (2.00–24.1) |
| t1/2, hours | 14.7 (24.3) | 25.04 (44.3) | 31.4 (60.0) | 34.0 (74.7) |
| CL/F, L/h | 3.77 (23.7) | 3.39 (43.8) | 2.38 (50.2) | 1.93 (55.7) |
| fu, % | 2.86 (15.1) | 2.65 (18.9) | 3.47 (19.9) | 3.96 (30.6) |
| AUCu, norm, kg·h/L | 0.643 (24.4) | 0.619 (43.5) | 1.21 (44.8) | 1.62 (50.1) |
| Cmax, u, norm, kg/L | 0.0224 (40.9) | 0.0153 (70.5) | 0.0204 (47.4) | 0.0269 (51.5) |
| AE, ur, % | 18.7 ± 7.29 | 11.0 ± 6.24 | 8.87 ± 2.98d | 4.16 ± 3.64e |
| CLR, L/h | 0.688 (56.9) | 0.367 (67.3) | 0.256 (39.9)d | 0.0670 (75.0)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 11 patients.
Data available from 8 patients.
Data available from 7 patients.