Safety, pharmacokinetics, and pharmacodynamics of avoralstat, an oral plasma kallikrein inhibitor: phase 1 study

Allergy. 2016 Dec;71(12):1676-1683. doi: 10.1111/all.12930. Epub 2016 Jul 20.


Background: Avoralstat is a potent small-molecule oral plasma kallikrein inhibitor under development for treatment of hereditary angioedema (HAE). This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of avoralstat.

Methods: This double-blind, placebo-controlled, ascending-dose cohort trial evaluated avoralstat single doses of 50, 125, 250, 500, and 1000 mg and multiple doses up to 2400 mg daily (100, 200, 400, and 800 mg every 8 h [q8 h] up to 7 days).

Results: Avoralstat (n = 71) was generally well tolerated with no signals for a safety concern; there were no serious adverse events (AEs) or discontinuations due to AEs, and compared to placebo (n = 18), no notable difference in AEs. Four moderate severity AEs were reported in two subjects; syncope after a single 250 mg dose (one subject) and abdominal pain, back pain, and eczema after multiple doses of 800 mg avoralstat (one subject). For multiple-dose cohorts, the incidence of gastrointestinal AEs was highest at the 2400 mg/day dose. Elimination of avoralstat was bi-exponential with a terminal half-life of 12-31 h. Inhibition of plasma kallikrein was observed at all doses, and the degree of inhibition was highly correlated with avoralstat concentrations (R = 0.93). Mean avoralstat concentrations at doses ≥400 mg q8 h met or exceeded plasma kallikrein EC50 values throughout the dosing interval.

Conclusion: Avoralstat was well tolerated, and drug exposure was sufficient to meet target levels for inhibition of plasma kallikrein. Based on these results, the 400 mg q8 h dose was selected for further evaluation in patients with HAE.

Keywords: avoralstat; hereditary angioedema; kallikrein inhibition.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Angioedemas, Hereditary / drug therapy*
  • Drug Administration Schedule
  • Drug Monitoring
  • Female
  • Humans
  • Male
  • Middle Aged
  • Plasma Kallikrein / antagonists & inhibitors*
  • Protease Inhibitors / administration & dosage*
  • Protease Inhibitors / adverse effects
  • Protease Inhibitors / pharmacokinetics*
  • Time Factors
  • Treatment Outcome
  • Young Adult


  • Protease Inhibitors
  • Plasma Kallikrein