1200 634500 2.09 1200 M$ 759000 2.5 104 week carcinogenicity 1200 F$ 510000 1.7 Rat 50 22150 0.07 2 weeks (Han Wistar) 150 81900 0.27 250 102550 0.34 2 trial 500 138000 0.46 1000 182000 0.60 2000 393000 1.30 50 0.06 13 trial 100 61100 0.20 200 167500 0.55 400 299500 0.99 400 240000 0.80 13 weeks 800 389500 1.30 1200 773000 2.55 50 31500 0.10 26 weeks 150 156500 0.52 600 344000 1.13 400 M$ 266000 0.88 104 week$ 400 F$ 510000 0.71 Marmosets 50 56500 0.19 1 week (Callithrix 250 242500 0.80 jacchus) 500 250500 0.83 25 0.10 52 trial 100 220000 0.73 200 441500 1.46 200 mg BID 151611 – 7 days (stable patients with HF) # = based on animal:human AUC values. Clinical plasma AUC0–12 h multiplied by 2 to compare with the animal AUC0-24h values; $ AUC0-24h values obtained from CTD. toxicities Sacubitril/valsartan complex was well tolerated in repeat dose studies in rat and monkey with little evidence of adverse effects. Target organs were identified as the gastrointestinal and the kidney. Changes were also noted in the heart. Sacubitril alone was well tolerated in repeat dose studies in mouse, rat and marmoset. The target organ in both rats and marmosets was the glandular stomach. Renal effects Juxtaglomerular hypertrophy/hyperplasia was observed following treatment with sacubitril/valsartan complex in all the monkey studies at mg/kg/day and in the 2 ≥100 week rat study at mg/kg/day. The effect was still present in monkeys after the ≥200 recovery period. The effect was not observed in longer rat studies which were conducted at mg/kg/day. Juxtaglomerular hypertrophy/hyperplasia is considered to be related ≤100
1200 634500 2.09 104 week carcinogenicity 1200 M$ 759000 2.5 1200 F$ 510000 1.7 Rat (Han Wistar) 2 weeks 50 22150 0.07 150 81900 0.27 2 250 102550 0.34 500 138000 0.46 1000 182000 0.60 2000 393000 1.30 13 50 0.06 100 61100 0.20 200 167500 0.55 400 299500 0.99 13 weeks 400 240000 0.80 800 389500 1.30 1200 773000 2.55 26 weeks 50 31500 0.10 150 156500 0.52 600 344000 1.13 104 week$ 400 M$ 266000 0.88 400 F$ 510000 0.71 Marmosets (Callithrix jacchus) 1 week 50 56500 0.19 250 242500 0.80 500 250500 0.83 52 25 0.10 100 220000 0.73 200 441500 1.46 (stable patients with HF) 7 days 200 mg BID 151611 – # = based on animal:human AUC values. Clinical plasma AUC0–12 h multiplied by 2 to compare with the animal AUC0-24h values; $ AUC0-24h values obtained from CTD. toxicities Sacubitril/valsartan complex was well tolerated in repeat dose studies in rat and monkey with little evidence of adverse effects. Target organs were identified as the gastrointestinal and the kidney. Changes were also noted in the heart. Sacubitril alone was well tolerated in repeat dose studies in mouse, rat and marmoset. The target organ in both rats and marmosets was the glandular stomach. Renal effects Juxtaglomerular hypertrophy/hyperplasia was observed following treatment with sacubitril/valsartan complex in all the monkey studies at ≥100 mg/kg/day and in the 2 week rat study at ≥200 mg/kg/day. The effect was still present in monkeys after the recovery period. The effect was not observed in longer rat studies which were conducted at ≤100 mg/kg/day. Juxtaglomerular hypertrophy/hyperplasia is considered to be related trial trial trial
161013_auspar-sacubitril-valsartan-salt-complex-160923.docx