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.

Bioavailability of Orally Administered Des-Aspartate-Angiotensin I in Human Subjects

“…Plasma samples were from subjects of a single-dose phase I trial on DAA-I [ 9 ]. The samples had been stored frozen at – 80 °C for a period of 18 months, prior to analysis.…”

“…This is probably attributed to its ability to cross Caco-2 cells via passive diffusion [ 8 ], indicating that it would cross intestinal epithelial cells, and its activity at concentrations lower than the Km of enzymes [ 1 ]. However in a single-dose phase I study, where subjects were orally administered a subefficacious, efficacious, and twice efficacious dose in terms of its preclinical hypoglycaemic activity, we found no significant increase in subjects’ plasma DAA-I concentration over a period of 12 h post-administration [ 9 ]. We have advanced various possibilities to explain the absence of DAA-I bioavailability in the phase I study.…”

Comment on: “A Single Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of Orally Administered Des-aspartate Angiotensin I in Healthy Subjects”

“…Des-aspartate angiotensin I (DAA-I) is a short-acting peptide molecule comprising nine amino acids, whose main role is to block angiotensin II via agonistic activity on the angiotensin AT1 receptor [ 1 ]. Lee et al recently reported the safety, tolerability and pharmacokinetics of DAA-1 in healthy subjects who received single escalating doses of DAA-1 in an extemporaneously prepared oral formulation [ 2 ]. This study in particular assumes importance primarily because hitherto no such human clinical pharmacology data pertaining to DAA-1 have been published [ 2 ].…”

“…Lee et al recently reported the safety, tolerability and pharmacokinetics of DAA-1 in healthy subjects who received single escalating doses of DAA-1 in an extemporaneously prepared oral formulation [ 2 ]. This study in particular assumes importance primarily because hitherto no such human clinical pharmacology data pertaining to DAA-1 have been published [ 2 ].…”

“…The safety and tolerability data gathered in this study showed no inadvertent effects and/or adverse events associated with DAA-1. However, the lack of differentiation in the single-dose pharmacokinetics of the examined three active doses in relation to placebo [ 2 ] poses a challenge in developing a cohesive clinical development plan for the advancement of DAA-1. Because of the rapid degradation of DAA-1, it was not expected that the first exogenous dose of DAA-1 at 0.08 mg/kg would show appreciable plasma levels in the human subjects [ 2 ].…”