title: Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects.
abstract: OBJECTIVE
  Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II (Ang1-8) to angiotensin 1-7 (Ang1-7), a functional antagonist of Ang1-8, with vasodilatory, antiproliferative, antiangiogenic, and anti-inflammatory properties. In conditions with an unbalanced renin-angiotensin-aldosterone system with elevated Ang1-8, administration of ACE2 has shown promising effects in a variety of animal models. Enhancing ACE2 activity by exogenous administration of ACE2 might also be beneficial in human diseases with pathologically elevated Ang1-8. As a first step we performed a first-in-man study to determine pharmacokinetics, pharmacodynamics, safety, and tolerability of recombinant ACE2 in healthy volunteers.
  
  
  METHODS
  Recombinant human ACE2 (rhACE2) was administered intravenously to healthy human subjects in a randomized, double-blind, placebo-controlled, single-dose, dose-escalation study followed by an open-label multiple-dose study. ACE2 concentrations were determined by quantifying ACE2 activity and ACE2 content in plasma samples. Concentrations of the angiotensin system effector peptides Ang1-8, Ang1-7, and Ang1-5 were determined using a liquid chromatography-tandem mass spectrometry method.
  
  
  RESULTS
  Single rhACE2 doses of 100-1,200 μg/kg caused a dose-dependent increase of systemic exposure with biphasic elimination and a dose-independent terminal half-life of 10 h. In all single-dose cohorts, Ang1-8 decreased within 30 min postinfusion, angiotensin 1-7 (Ang1-7) either increased (100 and 200 μg/kg doses), decreased, or remained unchanged (400-1,200 μg/kg doses), whereas angiotensin 1-5 (Ang1-5) transiently increased for all doses investigated. With the exception of the lowest rhACE2 dose, the decrease in Ang1-8 levels lasted for at least 24 h. Repeated dosing (400 μg/kg for 3 or 6 days) caused only minimal accumulation of ACE2, and Ang1-8 levels were suppressed over the whole application period.
  
  
  CONCLUSIONS
  Administration of rhACE2 was well tolerated by healthy human subjects. Exposure was dose dependent with a dose-independent terminal elimination half-life in the range of 10 h. Despite marked changes in angiotensin system peptide concentrations, cardiovascular effects were absent, suggesting the presence of effective compensatory mechanisms in healthy volunteers.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital Basel, 4031, Basel, Switzerland. manuel.haschke@unibas.ch
authors.forename: Manuel
authors.initials: M
authors.lastname: Haschke
authors.forename: Manfred
authors.initials: M
authors.lastname: Schuster
authors.forename: Marko
authors.initials: M
authors.lastname: Poglitsch
authors.forename: Hans
authors.initials: H
authors.lastname: Loibner
authors.forename: Marc
authors.initials: M
authors.lastname: Salzberg
authors.forename: Marcel
authors.initials: M
authors.lastname: Bruggisser
authors.forename: Joseph
authors.initials: J
authors.lastname: Penninger
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
mesh_terms: D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000085962:Angiotensin-Converting Enzyme 2; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000097:blood; D007703:Peptidyl-Dipeptidase A / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D010446:Peptide Fragments; D011994:Recombinant Proteins; C104454:angiotensin II (1-8); D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)