Table 4.
Midazolam study: pharmacokinetic parameters of midazolam following oral riociguat 2.5 mg 3 times daily ± midazolam 7.5 mg
| Midazolam 7.5 mg (n = 22) | Midazolam 7.5 mg + riociguat 2.5 mg (n = 22) | (Midazolam + riociguat)∶midazolam | ||||
|---|---|---|---|---|---|---|
| Parameter | Geometric mean (range) |
CV, % | Geometric mean (range) |
CV, % | Estimated ratio, %a | 90% CI |
| AUC, μg·h/L | 91.1 (48.8–169.0) | 34.3 | 98.2 (48.9–174.0) | 37 | 108.4 | 97.0–121.1 |
| Cmax, μg/L | 29.0 (17.2–70.6) | 45.1 | 29.5 (14.5–74.9) | 41.5 | 101.8 | 88.9–116.5 |
| tmax, hours | 1.0 (0.5–4.0) | … | 1.0 (0.5–4.0) | … | … | … |
| t1/2, hours | 4.5 (2.2–8.3) | 35.9 | 4.3 (2.6–9.4) | 34.9 | … | … |
Data are means, except tmax, which is a median. ANOVA: analysis of variance; AUC: area under the plasma concentration–time curve; CI: confidence interval; Cmax: maximum midazolam plasma concentration; CV: coefficient of variation; tmax: time to reach Cmax; t1/2: elimination half-life.
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 (midazolam + riociguat)∶riociguat ratios of these kinetic parameters were calculated by retransformation of the logarithmic results (given by the ANOVA) using the intraindividual standard deviation.