mg/kg/day ng·h/mL sacubitrilat Rat Fertility and early (Han Wistar) 150 41700a 0.13 embryonic development sacubitrilat Rat Embryofoetal (Han Wistar) 30 0.02 development 5950 100 0.06 19200 200 0.10 29400 Valsartan 30 0.16 13400 100 0.72 60000 200 1.44 119000 sacubitrilat Rabbit Embryofoetal (NZW) 3 0.02 development 1930 10 0.03 8920 30 0.34 102000 Valsartan 3 0.50 41100 10 2.04 169000 30 4.83 400000 Human 200 mg BID sacubitrilat Treatment for 7 (stable patients 151611* – days with HF) Valsartan 41388* – *AUC0–12 h; # = based on animal:human AUC values. Clinical plasma AUC0–12 h multiplied by 2 to compare with the animal AUC0-24h values; a AUC value based on linear extrapolation from 100 mg/kg/day exposure on day 76 in rat study (0670283). Table 6. Relative exposure in reproductive and developmental toxicity studies with sacubitril. Species Study type Dose AUC0-24h ER# & strain mg/kg/day ng·h/mL sacubitrilat Rat Fertility and early (Han Wistar) 750 365150a 1.20 embryonic development sacubitrilat Embryofoetal 75 0.20 development 60300 250 0.19 58700
mg/kg/day ng·h/mL Rat (Han Wistar) Fertility and early embryonic development sacubitrilat 150 41700a 0.13 Rat (Han Wistar) Embryofoetal development sacubitrilat 30 5950 0.02 100 19200 0.06 200 29400 0.10 Valsartan 30 13400 0.16 100 60000 0.72 200 119000 1.44 Rabbit (NZW) Embryofoetal development sacubitrilat 3 1930 0.02 10 8920 0.03 30 102000 0.34 Valsartan 3 41100 0.50 10 169000 2.04 30 400000 4.83 Human (stable patients with HF) Treatment for 7 days 200 mg BID sacubitrilat 151611* – Valsartan 41388* – *AUC0–12 h; # = based on animal:human AUC values. Clinical plasma AUC0–12 h multiplied by 2 to compare with the animal AUC0-24h values; a AUC value based on linear extrapolation from 100 mg/kg/day exposure on day 76 in rat study (0670283). Table 6. Relative exposure in reproductive and developmental toxicity studies with sacubitril. Species & strain Study type Dose mg/kg/day AUC0-24h ng·h/mL ER# Rat (Han Wistar) Fertility and early embryonic development sacubitrilat 750 365150a 1.20 Embryofoetal development sacubitrilat 75 60300 0.20 250 58700 0.19
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