A Single Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of Orally Administered Des-Aspartate Angiotensin I in Healthy Subjects

Abstract

Des-aspartate-angiotensin I (DAA-I) is an endogenous angiotensin peptide and a prototype angiotensin receptor agonist (ARA). It acts on the angiotensin AT1 receptor and antagonises the deleterious actions of angiotensin II. DAA-I attenuates animal models of human disease in which angiotensin II has been implicated, such as cardiac hypertrophy, neointima formation, arteriosclerosis, renal failure, post-infarction injuries, diabetes, viral infection, chemical-induced inflammation, heat stroke, cancer, and gamma radiation lethality. DAA-I crosses Caco-2 cells and is effective at sub-nanomolar concentrations. These two properties are responsible for its oral efficacy. A single dose-escalation study was conducted to evaluate the safety, tolerability and pharmacokinetics of orally administered DAA-I in 18 healthy subjects. DAA-I was safe and well tolerated by the subjects, who were administered either 0.08, 0.70 or 1.50 mg/kg of the compound. The heart rate and systolic and diastolic blood pressures determined at each post-dose measurement remained within the clinically acceptable range. Across all cohorts, DAA-I had no substantial effect on blood pressures compared with placebo. Electrocardiographs (ECGs) were normal, and none of the subjects complained of chest discomfort. All clinical laboratory tests obtained before and after DAA-I and placebo treatment were normal. Pharmacokinetic analysis over a 12-h period following DAA-I administration did not show any increase of its level beyond basal concentration. This is in line with studies showing that intravenously administered DAA-I is rapidly metabolized and has a short half-life. We postulate that, during its short systemic sojourn, DAA-I exerts its actions via biased agonism on the angiotensin AT1 receptor.The ClinicalTrial.gov assignment number for this study is NCT02666196.

Conflict of interest statement

Compliance with Ethical Standards Funding The study was supported by Grant R-184-000-237-511 from the National Medical Research Council, Singapore. Conflict of interest All the authors have no conflicts of interest with regard to financial sponsorship or governmental guidelines on the publication of this manuscript.

Figures

Fig. 1

Plot of averaged plasma DAA-I concentration vs. sampling time. Top panel plot of cohort 1 subjects who received either 0.08 mg/kg DAA-I (four subjects) or placebo (two subjects). Middle panel plot of cohort 2 subjects who received either 0.70 mg/kg DAA-I (four subjects) or placebo (two subjects). Bottom panel plot of cohort 3 subjects who received either 1.5 mg/kg DAA-I (four subjects) or placebo (two subjects)