Safety, Tolerability and Pharmacokinetic Data of the Novel Orally Active Formulation of Angiotensin-(1-7), Hydroxypropyl-beta-cyclodextrin/Ang-(1-7), in Healthy Volunteers-A Randomized Double-blinded Controlled Pilot Study

Angiotensin-(1-7) is an endogenous peptide of the renin-angiotensin system in humans. It has several properties, which make it of great interest for healthcare, such as in systemic/ pulmonary hypertension treatment, insulin resistance improvement, reduction of visceral obesity and cardiac remodeling and arrhythmias. In this randomized double-blinded controlled phase I study we aimed to determine safety, tolerability, and pharmacokinetic properties of the new drug, angiotensin-(1-7) included in Hydroxypropyl β-cyclodextrin [Ang(1-7)/HPβCD)] in healthy adult volunteers, who were recruited in accordance to inclusion and exclusion criteria. Thirty-two volunteers ( 18-40 years-old ) were admitted to a hospital clinical research ward and remained under observation for two days, during which they received a single oral dose of Ang(1-7)HPβCD (equivalent to 0.35, 1.75 or 7.0 mg of the peptide) or placebo (N=8/ group). Vital signs and side effects were recorded according to the study protocol and blood samples were collected to obtain the pharmacokinetic profile of Ang-(1-7using LC/MS/MS. The oral administration of the novel compound Ang-(1-7)/HPβCD caused a dose-dependent elevation in the Ang-(1-7) plasma levels with a Tmax of 6.5±0.6 hours. The medians of the area under the curve for the placebo, 0.35, 1.75 and 7.0 mg doses were (in pg/mL/24 hours): 837.5±139.8 , 1094.4±224.3, 1415.0±187.7 and 1719.4±304.9, respectively. The Cmax for the 0.35, 1.75 and 7.0 mg doses were 26.1±3.17 pg/mL, 30.7±4.18pg/mL and 44.1±7.42 pg/mL, respectively. We did not find any statistically significant differences among the clinical and laboratorial parameters before and after the study. There were few mild side effects reported in the study, not related to the dose: two volunteers reported headache (one in the placebo group and one in the 0,35mg group) and three had dizziness and sweating in the orthostatic position (one in the 0.35 and two in the 1.75mg group). Our data show that the novel Ang-(1-7)/HPβCD formulation allow the absorption of Ang-(1-7), and is safe and well tolerated. Our results open new perspectives for future clinical trials with Ang-(1-7)/HPβCD for the treatment of arterial hypertension and other conditions.