PNA5, a glycosylated angiotensin-(1−7) mas receptor agonist for vascular dementia: A two species toxicology and toxicokinetic study

PNA5 is a novel pleotropic anti-inflammatory glycosylated-Angiotensin-(1-7) peptide derivative with outstanding brain penetration and enhanced bioavailability. PNA5, via the Mas receptor, decreases brain and cerebrovascular inflammation, reduces reactive oxygen species and inflammatory cytokines production, improves cerebral blood flow, and restores cognitive function in our mouse model of VCID (Vascular contributions to cognitive impairment and dementia). This study evaluated the potential systemic and local toxicity and toxicokinetic (TK) of PNA5 following daily subcutaneous administration in Sprague Dawley rats and Beagle dogs for 28 consecutive days. PNA5 was given at 1, 5, 40 mg/kg/day to rats (n = 12) and at 1, 5, and 20 mg/kg/day in dogs (n = 6) once daily for 28 consecutive days. Blood samples were collected on days 1 and 28 for TK analysis. PNA5 was well tolerated at all doses in both species, with no test article-related mortality or adverse effects. Systemic exposure to PNA5 appeared to be independent of sex. In rats, Cmax and AUC_0-2hr values increased with increasing doses. Systemic exposure to PNA5 in rats was greater on day 28 compared to day 1 following repeated administration of PNA5. In dogs, Cmax values increased less than dose-proportionally, and AUC_0-2hr increased approximately dose-proportionally on days 1 and 28. Systemic exposure to PNA5 in dogs was similar on days 1 and 28 following repeated administration. These results show that PNA5 has no toxicological effects at the highest doses tested in rats or dogs and is well tolerated with repeated exposure for 28 days. Accumulation was observed in rats but not in dogs.