Species | Duration | Sex | Dose | ||||
---|---|---|---|---|---|---|---|
mg/kg | |||||||
Rat | 4 wka | 0 | 50 | 150 | 450 | 1500 | |
M | 25 ± 11 (11–46) | 20 ± 6.6 (6.6–45) | 21 ± 8.9 (9.4–34) | 25 ± 9.1 (12–40) | 24 ± 12 (10–40) | ||
F | 20 ± 8.1 (12–40) | 25 ± 8.8 (8.8–45) | 27 ± 9.9 (8.9–34) | 28 ± 9.3 (16–39) | 37 ± 33 (13–128) | ||
26 wkb | 0 | 10 | 50 | 250 | |||
M | 32 ± 15 (11–57) | 17 ± 6.6 (9.4–27) | 23 ± 10 (10–52) | 19 ± 9.3 (6.5–28.9) | |||
F | 49 ± 27 (19–124) | 32 ± 16 (13–81) | 37 ± 31 (11–125) | 30 ± 16 (11–58) | |||
Dog | 4 wkc | 0 | 10 | 50 | 250 | ||
M | 8.3 ± 1.3 (7.2–10) | 7.3 ± 0.4 (7.0–7.7) | 6.6 ± 0.8 (6.0–7.5) | 7.7 ± 3.3 (6.3–12)d | |||
F | 15 ± 10 (8.3–33) | 15 ± 8.2 (8.1–24) | 7.8 ± 1.6 (6.6–9.6) | 9.0 ± 3.9 (6.2–16) | |||
13 wk | 0 | 2 | 5 | 30 | 100 | ||
Me | 2.8 ± 2.3 (BLQ–7.7)f | 1.0 ± 0.6 (BLQ–2.3) | 1.6 ± 0.9 (BLQ–2.7) | 1.2 ± 0.9 (BLQ–3.1) | BLQg | ||
F | 1.5 ± 0.5 (BLQ–2.0) | 3.5 ± 3.7 (BLQ–2.3) | 1.9 ± 0.9 (BLQ–2.3) | 1.9 ± 0.8 (BLQ–3.4) | 1.8 ± 1.5 (BLQ–3.9) | ||
Mh | BLQg | BLQg | 1.3 ± 1.1 (BLQ–3.5) | 1.9 ± 1.4 (BLQ–4.0) | 1.8 ± 2.4 (BLQ–7.2) | ||
F | 3.2 ± 3.6 (BLQ–9.7) | 1.7 ± 1.2 (BLQ–3.1) | BLQg | BLQg | 4.9 ± 8.7 (BLQ–6.2)i | ||
39 wkj | 0 | 5 | 30 | 100/75k | |||
M | 1.4 ± 1.9 (0.2–5.9) | 2.0 ± 3.7 (0.3–11.1) | 0.5 ± 0.3 (0.1–1.0) | 0.7 ± 0.8 (BLQ–1.9)l,m |
BLQ, below the limit of quantification.
↵a n = 10. Data are from day 28 of the 4-week study, all data are mean ± S.D. (range).
↵b n = 15. Data are from the last day of macitentan treatment.
↵c Data are from day 23 of the 4-week study. n = 5 in the control and 250-mg/kg dose groups, and n = 3 in the 10- and 50-mg/kg dose groups.
↵d One sample missing; mean and S.D. of n = 4.
↵e n = 7. Data are from week 4 of the 13-week study.
↵f BLQ: 1.5 μM.
↵g n = 7. Data are from the last treatment week of the 13-week study.
↵h All animals BLQ.
↵i One apparent outlier with plasma bile salts of 24 μM at study end, included in the calculation of mean and S.D. but not in range; liver specimens were unremarkable in the subsequent histologic examination.
↵j n = 8. Data are from the last treatment week of the 39-week study.
↵k The high dose was reduced from 100 to 75 mg/kg in week 20.
↵l n = 6–7.
↵m BLQ: 0.5 μM.