TABLE 5

Serum bile salts (in μM) in rat and dog toxicity studies with macitentan

Species	Duration	Sex	Dose
			mg/kg
Rat	4 wk^{^a}		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 wk^{^b}		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 wk^{^c}		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
		M^{^e}	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)	BLQ^{^g}
		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)
		M^{^h}	BLQ^{^g}	BLQ^{^g}	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)	BLQ^{^g}	BLQ^{^g}	4.9 ± 8.7 (BLQ–6.2)ⁱ
	39 wk^{^j}		0	5	30	100/75^{^k}
		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.