Risk and safety assessment of exogenous human brain natriuretic peptide in cynomolgus monkeys (Macaca fascicularis)-A subchronic study

Safety evaluation of synthetic human brain natriuretic peptide (shBNP) was carried out in cynomolgus monkeys (Macaca fascicularis) by 2-week intravenous toxicity studies. System exposure was also assessed throughout the whole administration. Three test groups received doses of 432, 1440 and 4320 μg/kg/day of shBNP, with a high infusion rate of 36 mL/kg/hr for 30 min compared to the clinical protocol of continuous infusion over 24 h. Commercially available recombinant human brain natriuretic peptide (rhBNP) of 1440 μg/kg/day was used as positive control. The 2-week repeated intravenous doses of shBNP resulted in reversible increased serum LDH and CPK in monkeys receiving 1440 and 4320 μg/kg/day dose with no pertinent histopathological changes. Some changes related to the pharmacologic effects of BNP including hypotension was observed after administration. No treatment-related mortalities or renal dysfunction were found. Controversy about the safety issue of BNP as an exogenous hormone concerning ventricular remodeling and myocardial cell apoptosis, coupled with our results, were also discussed. The no-observed-adverse-effect level (NOAEL) was considered to be 432 μg/kg /day, which is about 20 times higher than the commonly used clinical dose. The results of the present study advocate the safety of shBNP in cynomolgus monkeys at levels used in the study.