Table 2.
Pharmacokinetic parameters for riociguat following a single oral dose of riociguat 0.5 mg ± ketoconazole 400 mg
| Riociguat 0.5 mg (n = 16) | Riociguat 0.5 mg + ketoconazole 400 mg (n = 16) | (Riociguat + ketoconazole)∶riociguat | ||||
|---|---|---|---|---|---|---|
| Parameter | Geometric mean (range) |
CV, % | Geometric mean (range) |
CV, % | Estimated ratio, %a | 90% CI |
| AUC0-∞, μg·h/L | 81.9 (19.6–218.7) | 78.6 | 204.9 (91.9–409.5) | 44.9 | 250.1 | 214.1–292.3 |
| Cmax, μg/L | 9.4 (5.2–14.0) | 29.9 | 13.7 (9.8–17.8) | 19.3 | 146.0 | 135.3–157.6 |
| tmax, hours | 2.0 (1.0–6.0) | … | 3.0 (1.0–4.0) | … | … | … |
| t1/2, hours | 7.4 (1.2–22.8) | 78.5 | 9.2 (3.6–22.6) | 57.1 | … | … |
| Aeur, % | 7.9 (1.6–13.8) | 4.0 | 17.1 (3.3–27.3) | 6.5 | … | … |
| MRT, hours | 10.2 (3.7–24.0) | 53.7 | 15.1 (7.3–29.5) | 39.4 | … | … |
| Vz/f, L | 64.7 (45.4–100.3) | 26.7 | 32.3 (19.0–50.8) | 29.7 | … | … |
| CL/f, L/h | 6.1 (2.3–25.6) | 78.6 | 2.4 (1.2–5.4) | 44.9 | … | … |
Data are means, except tmax, which is a median. Aeur: amount excreted via urine; ANOVA: analysis of variance; AUC0-∞: area under the plasma concentration–time curve; CI: confidence interval; CL/f: total riociguat clearance from plasma; Cmax: maximum riociguat plasma concentration; CV: coefficient of variation; MRT: mean residence time; tmax: time to reach Cmax; t1/2: elimination half-life; Vz/f: apparent volume of distribution during terminal phase after oral administration.
The logarithms of AUC0-∞/dose and Cmax/dose of riociguat were analyzed with an ANOVA including subject and treatment effects. On the basis of these analyses, point estimates (least square means) and exploratory 90% CIs for the (ketoconazole + riociguat)∶riociguat ratios of these kinetic parameters were calculated by retransformation of the logarithmic results (given by the ANOVA) using the intraindividual standard deviation.