Table 5.
Pharmacokinetic parameters for vericiguat following multiple administrations of vericiguat 1.25–10 mg QD as IR tablets, in the fasted state (day 11; study MD1)
| Parameter | Vericiguat dose (IR tablets) | |||||||
|---|---|---|---|---|---|---|---|---|
| 1.25 mg (n = 9) | 5.0 mg (n = 8)a | 7.5 mg (n = 9) | 10.0 mg (n = 9) | |||||
| Geometric mean (range) | CV, % | Geometric mean (range) | CV, % | Geometric mean (range) | CV, % | Geometric mean (range) | CV, % | |
| Cmax,ss, μg L−1 | 89 (69.3–132) | 18.6 | 289 (214–391) | 25.1 | 407 (296–582) | 24.2 | 472 (303–726) | 30.6 |
| Cmax,ss,norm, kg L−1 | 4.54 (3.63–5.64) | 16.7 | 3.19 (2.31–4.27) | 20.0 | 3.57 (2.87–4.41) | 14.5 | 3.02 (1.79–4.11) | 27.5 |
| AUCτ,ss, μg h L−1 | 1170 (978–1570) | 14.5 | 3670 (2660–5130) | 23.4 | 4810 (2790–6460) | 27.6 | 6170 (4160–9790) | 29.9 |
| AUCτ,ss,norm, kg h L−1 | 59.4 (44.2–73.6) | 14.7 | 40.5 (31.3–53.2) | 19.8 | 42.2 (26.8–48.9) | 20.2 | 39.6 (24.5–55.5) | 28.2 |
| tmaxb, h | 1.00 (0.75–2.50) | – | 1.75 (0.75–4.00) | – | 2.50 (0.75–2.50) | – | 2.50 (0.75–2.50) | – |
| t1/2, h | 27.0 (17.6–37.4) | 23.6 | 23.5 (15.8–34.4) | 30.6 | 22.1 (17.5–27.3) | 15.9 | 20.7 (16.3–31.4) | 25.2 |
| RAAUC | 1.66 (1.32–2.09) | 13.3 | 1.44 (1.23–1.78) | 13.1 | 1.49 (1.22–2.14) | 19.1 | 1.40 (0.92–2.49) | 27.2 |
| RACmax | 1.44 (0.98–2.65) | 29.5 | 1.16 (0.90–1.42) | 13.8 | 1.26 (0.94–2.02) | 23.7 | 1.29 (0.86–2.40) | 27.2 |
| RLIN | 0.98 (0.88–1.13) | 8.47 | 0.89 (0.75–1.14) | 13.0 | 0.94 (0.72–1.28) | 20.0 | 0.83 (0.63–1.41) | 22.9 |
| AE,ur(0–24)c,d, % | 6.04 (2.40–9.35) | 2.02¶ | 5.18 (3.43–7.36) | 1.53e | 4.75 (2.41–6.71) | 1.24e | 5.01 (2.16–8.38) | 1.99e |
| CLR§, L h−1 | 0.06 (0.03–0.09) | 36.6¶ | 0.07 (0.04–0.10) | 31.8e | 0.07 (0.06–0.09) | 12.7e | 0.08 (0.05–0.11) | 22.4e |
| CLss/f, L h−1 | 1.07 (0.80–1.28) | 14.5 | 1.36 (0.97–1.88) | 23.4 | 1.56 (1.16–2.69) | 27.6 | 1.62 (1.02–2.41) | 29.9 |
aOne subject withdrew after day 5
bMedian (range)
cn = 8 for AE,ur(0–24) and CLR at doses of 1.25 and 7.5 mg
dValues are arithmetic mean
eValues are standard deviation
AE,ur(0–24), rate of amount of drug excreted into urine from 0 to 24 h after administration to the administered dose; AUC, area under the plasma concentration versus time curve from zero to infinity after single (first) dose; AUCτ,ss, AUC during any dosing interval at steady state; AUCτ,ss,norm, AUCτ,ss divided by dose (mg) per kg body weight; CLss/f, total body clearance of drug from plasma calculated after oral administration (apparent oral clearance) after steady state; Cmax,ss, maximum drug concentration in plasma at steady state during a dosage interval; Cmax,ss,norm, maximum drug concentration in plasma at steady state during a dosage interval divided by dose (mg) per kg body weight; CV, coefficient of variation; IR, immediate release; MD1, multiple-dose study 1; QD, once daily; RAAUC, accumulation ratio calculated from AUCτ after multiple dosing and AUCτ after single dosing; RACmax, accumulation ratio calculated from Cmax after multiple dosing and Cmax after single dosing; RLIN, linearity factor of pharmacokinetics after multiple administration of identical doses calculated from AUCτ after multiple dosing and AUC after single dosing; tmax, time to reach maximum drug concentration in plasma after single (first) dose; t1/2, half-life associated with the terminal slope