Monkey sacubitrilat 1 week (Cynomolgus) 25 0.10 100 163500 0.54 Valsartan 25 5500 0.07 100 17000 0.21 sacubitrilat 2 weeks 100 258500 0.85 300 1160000 3.85 600 3500000 11.5 Valsartan 100 24700 0.30 300 127550 1.54 600 381000 4.60 sacubitrilat 13 trial 30 35900 0.12 100 161000 0.5 300 821000 2.71 Valsartan 30 5285 0.06 100 16500 0.20 300 72600 0.88 sacubitrilat 39 weeks 30 27200 0.18 100 152000 0.50 300 614000 2.02 Valsartan 30 8500 0.10 100 37650 0.45 300 67500 0.82 200 mg BID Human sacubitrilat 7 days (stable 151611* - patients with Valsartan HF) - * AUC0-12h values: were multiplied by 2 for comparison with the animal AUC0-24h and calculation of the Exposure Ratio. Table 4. Relative exposure in repeat-dose toxicity studies with sacubitril. Species duration Dose AUC0–24 h Exposure ( mg/kg/day) (ng∙h/mL) ratio# sacubitrilat 400 108500 0.35 Mouse 13 weeks (CD1) 800 257500 0.85
Monkey (Cynomolgus) 1 week sacubitrilat 25 0.10 100 163500 0.54 Valsartan 25 5500 0.07 100 17000 0.21 2 weeks sacubitrilat 100 258500 0.85 300 1160000 3.85 600 3500000 11.5 Valsartan 100 24700 0.30 300 127550 1.54 600 381000 4.60 13 sacubitrilat 30 35900 0.12 100 161000 0.5 300 821000 2.71 Valsartan 30 5285 0.06 100 16500 0.20 300 72600 0.88 39 weeks sacubitrilat 30 27200 0.18 100 152000 0.50 300 614000 2.02 Valsartan 30 8500 0.10 100 37650 0.45 300 67500 0.82 Human (stable patients with HF) 7 days 200 mg BID sacubitrilat 151611* - Valsartan - * AUC0-12h values: were multiplied by 2 for comparison with the animal AUC0-24h and calculation of the Exposure Ratio. Table 4. Relative exposure in repeat-dose toxicity studies with sacubitril. Species duration Dose ( mg/kg/day) AUC0–24 h (ng∙h/mL) Exposure ratio# sacubitrilat Mouse (CD1) 13 weeks 400 108500 0.35 800 257500 0.85 trial