Relative exposure Relative exposures to ACT-333679/selexipag were calculated relative to estimated AUC024 h values from population PK analysis of data from PAH patients steady-state selexipag doses of 1600 µg bd. Relative exposures to ACT-333679, at the No observable adverse effect level (NOAEL) dose, were moderately high for rodents (approximately40 for daily dosing of mice for 2 years and approximately15 for daily dosing of rats for 6 months) and very high for dogs (approximately140 for daily dosing for 9 months) (see Table 2). 2: Relative exposure in repeat-dose toxicity and carcinogenicity studiesa Study Study Dose Sex Exposure h ratioc, d day µg∙h/mLc of TK b 13 100e, 12.40, 34, 141, ♂ e weeks 300, 51.50, 195 (91) 500 71.50 (110, 469, (12.20, 811) 52.10, 90.00) 9.990, 27, 109, ♀ 39.80, 158 58.00 (91, 400, (10.10, 667) 44.40, 74.00) 2 years 125, 13.90, 38, 87, ♂ (181) 250, 31.70, 184 500f 67.50 (105, 332, (11.60, 760) 36.80, 84.40) 16.00, 44, 84, ♀ 30.80, 179 65.50 (168, 331, (18.60, 826) 36.70, 91.70) Rat 4 20, 12.20, 33, 106, ♂ (SD) weeks 60, 38.79, 375 (28) 180 137.3 (3, 19, 79) (0.3176, 2.148, 8.770) 9.541, 26, 99, ♀ 36.28, 829 303.5 (5, 26, (0.5100, 223)
Relative exposure Relative exposures to ACT-333679/selexipag were calculated relative to estimated AUC024 h values from population PK analysis of data from PAH patients steady-state selexipag doses of 1600 µg bd. Relative exposures to ACT-333679, at the No observable adverse effect level (NOAEL) dose, were moderately high for rodents (approximately40 for daily dosing of mice for 2 years and approximately15 for daily dosing of rats for 6 months) and very high for dogs (approximately140 for daily dosing for 9 months) (see Table 2). 2: Relative exposure in repeat-dose toxicity and carcinogenicity studiesa Study Study day of TK Dose Sex h µg∙h/mLc Exposure ratioc, d 13 weeks (91) 100e, 300, 500 ♂ 12.40, 51.50, 71.50 (12.20, 52.10, 90.00) 34, 141, 195 (110, 469, 811) ♀ 9.990, 39.80, 58.00 (10.10, 44.40, 74.00) 27, 109, 158 (91, 400, 667) 2 years (181) 125, 250, 500f ♂ 13.90, 31.70, 67.50 (11.60, 36.80, 84.40) 38, 87, 184 (105, 332, 760) ♀ 16.00, 30.80, 65.50 (18.60, 36.70, 91.70) 44, 84, 179 (168, 331, 826) Rat (SD) 4 weeks (28) 20, 60, 180 ♂ 12.20, 38.79, 137.3 (0.3176, 2.148, 8.770) 33, 106, 375 (3, 19, 79) ♀ 9.541, 36.28, 303.5 (0.5100, 26, 99, 829 (5, 26, 223) b e
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