title: Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers.
abstract: OBJECTIVE
  Activated Protein C (APC) stimulates multiple cytoprotective pathways via the protease activated receptor-1 (PAR-1) and promotes anticoagulation. 3K3A-APC was designed for preserved activity at PAR-1 with reduced anticoagulation. This Phase 1 trial characterized pharmacokinetics and anticoagulation effects of 3K3A-APC.
  
  
  METHODS
  Subjects (n=64) were randomly assigned to receive 3K3A-APC (n=4) at 6, 30, 90, 180, 360, 540 or 720 µg/kg or placebo (n=6) and were observed for 24 hr. After safety review additional subjects received drug every 12 hr for 5 doses (n=6 per group) at 90, 180, 360, or 540 µg/kg or placebo (n=8) and were observed for 24 hr.
  
  
  RESULTS
  All subjects returned for safety assessments at 72 hours and 15 days. We found few adverse events in all groups. Systolic blood pressure increased in both active and placebo groups. Moderately severe headache, nausea and vomiting were reported in one of two subjects treated with 720 µg/kg so 540 µg/kg was considered the highest tolerated dose. Mean plasma concentrations increased in proportion to dose. Clearance ranged from 11,693 ± 807 to 18,701 ± 4,797 mL/hr, volume of distribution ranged from 4,873±828 to 6,971 ± 1,169 mL, and elimination half-life ranged from 0.211 ± 0.097 to 0.294 ± 0.054 hours. Elevations in aPTT were minimal.
  
  
  CONCLUSIONS
  3K3A-APC was well tolerated at multiple doses as high as 540 µg/kg. These results should be confirmed in stroke patients with relevant co-morbidities. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01660230.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lyden
authors.forename: Howard
authors.initials: H
authors.lastname: Levy
authors.forename: Sara
authors.initials: S
authors.lastname: Weymer
authors.forename: Kent
authors.initials: K
authors.lastname: Pryor
authors.forename: William
authors.initials: W
authors.lastname: Kramer
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Davis
authors.affiliation: Department of Neurology, 8700 Beverly Blvd, Los Angeles, CA 90048. Lydenp@cshs.org.
authors.forename: Berislav
authors.initials: B
authors.lastname: Zlokovic
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015331:Cohort Studies; D064368:Healthy Volunteers; D006801:Humans; D010919:Placebos; D011486:Protein C / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: C000591161:3K3A-APC protein; D000925:Anticoagulants; D010919:Placebos; D011486:Protein C; D011994:Recombinant Proteins