title: Safety, pharmacokinetics, and pharmacodynamics of avoralstat, an oral plasma kallikrein inhibitor: phase 1 study.
abstract: 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.
  
  
  
  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).
  
  
  
  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 EC50values throughout the dosing interval.
  
  
  
  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.
authors.affiliation: BioCryst Pharmaceuticals, Durham, NC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cornpropst
authors.affiliation: BioCryst Pharmaceuticals, Durham, NC, USA.
authors.forename: P
authors.initials: P
authors.lastname: Collis
authors.affiliation: Quotient Clinical Ltd, Nottingham, UK.
authors.forename: J
authors.initials: J
authors.lastname: Collier
authors.affiliation: BioCryst Pharmaceuticals, Birmingham, AL, USA.
authors.forename: Y S
authors.initials: YS
authors.lastname: Babu
authors.affiliation: BioCryst Pharmaceuticals, Birmingham, AL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Wilson
authors.affiliation: BioCryst Pharmaceuticals, Birmingham, AL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: PharStat Inc., Durham, NC, USA.
authors.forename: L
authors.initials: L
authors.lastname: Fang
authors.affiliation: PharStat Inc., Durham, NC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zong
authors.affiliation: BioCryst Pharmaceuticals, Durham, NC, USA.
authors.forename: W P
authors.identifier: 0000-0001-8320-1323
authors.initials: WP
authors.lastname: Sheridan
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D054179:Angioedemas, Hereditary / Q000188:drug therapy*; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020842:Plasma Kallikrein / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D011480:Protease Inhibitors; D020842:Plasma Kallikrein
keywords: avoralstat; hereditary angioedema; kallikrein inhibition