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Preclinical safety and pharmacokinetic profile of 3K3A-APC, a novel, modified activated protein C for ischemic stroke

Academic Article
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Overview

authors

  • Williams, P. D.
  • Zlokovic, B. V.
  • Griffin, John
  • Pryor, K. E.
  • Davis, T. P.

publication date

  • September 2012

journal

  • Current Pharmaceutical Design  Journal

abstract

  • Activated protein C (APC), a protease with anticoagulant and cytoprotective activities, protects neurons and cerebrovascular endothelium from ischemic injury. A recombinant APC, drotrecogin alfa (activated) (DrotAA) (Xigris®), was approved by the Food and Drug Administration for the treatment of sepsis; however, serious bleeding was a dose-limiting side effect. A modified APC, containing 405 amino acid residues, 3K3A-APC, was designed to possess significantly reduced anticoagulant activity ( < 10 %) while maintaining full cytoprotective properties. The preclinical safety assessment of 3K3A-APC was conducted to support initiation of ischemic stroke clinical trials.The safety and toxicokinetics of 3K3A-APC were studied in CD-1 mice and cynomolgus monkeys. Multiple-dose (14-day), intravenous GLP toxicology assessed toxicity, histopathology, immunogenicity, and toxicokinetics.Dose-related increases in plasma total 3K3A-APC were observed in mice and monkeys with no evidence of accumulation over 14 days. The elimination T(1/2) in monkeys was 1 hour. 3K3A-APC was well tolerated in mice and monkeys, and no signs of 3K3A-APC toxicity were identified in mice or monkeys at any time. Additionally,wild-type APC (DrotAA) was studied to obtain comparative anticoagulant data using clotting assays. Anticoagulant activity of 3K3A-APC was observed in monkeys at doses of 1 and 5 mg/kg/day .In contrast, DrotAA showed prolongation of clotting assays in monkeys at doses 1/10(th) of those showing effects with 3K3A-APC. Based upon the anticoagulant profiles, the risk for APC-induced bleeding in clinical trials of 3K3A-APC is greatly reduced relative to wild type APC which makes this new drug a feasible therapy for ischemic stroke patients.
  • Activated protein C (APC), a protease with anticoagulant and cytoprotective activities, protects neurons and cerebrovascular endothelium from ischemic injury. A recombinant APC, drotrecogin alfa (activated) (DrotAA) (Xigris�), was approved by the Food and Drug Administration for the treatment of sepsis; however, serious bleeding was a dose-limiting side effect. A modified APC, containing 405 amino acid residues, 3K3A-APC, was designed to possess significantly reduced anticoagulant activity ( < 10 %) while maintaining full cytoprotective properties. The preclinical safety assessment of 3K3A-APC was conducted to support initiation of ischemic stroke clinical trials.The safety and toxicokinetics of 3K3A-APC were studied in CD-1 mice and cynomolgus monkeys. Multiple-dose (14-day), intravenous GLP toxicology assessed toxicity, histopathology, immunogenicity, and toxicokinetics.Dose-related increases in plasma total 3K3A-APC were observed in mice and monkeys with no evidence of accumulation over 14 days. The elimination T(1/2) in monkeys was 1 hour. 3K3A-APC was well tolerated in mice and monkeys, and no signs of 3K3A-APC toxicity were identified in mice or monkeys at any time. Additionally,wild-type APC (DrotAA) was studied to obtain comparative anticoagulant data using clotting assays. Anticoagulant activity of 3K3A-APC was observed in monkeys at doses of 1 and 5 mg/kg/day .In contrast, DrotAA showed prolongation of clotting assays in monkeys at doses 1/10(th) of those showing effects with 3K3A-APC. Based upon the anticoagulant profiles, the risk for APC-induced bleeding in clinical trials of 3K3A-APC is greatly reduced relative to wild type APC which makes this new drug a feasible therapy for ischemic stroke patients.

subject areas

  • Amino Acid Sequence
  • Animals
  • Anticoagulants
  • Blood Coagulation
  • Blood Coagulation Tests
  • Brain Ischemia
  • Dose-Response Relationship, Drug
  • Feasibility Studies
  • Female
  • Half-Life
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Inbred ICR
  • Protein C
  • Recombinant Proteins
  • Species Specificity
  • Stroke
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Research

keywords

  • Neuroprotection
  • anticoagulant activity
  • pharmacokinetics
  • toxicology
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Identity

PubMed Central ID

  • PMC3472038

International Standard Serial Number (ISSN)

  • 1381-6128

Digital Object Identifier (DOI)

  • 10.2174/138161212802430413

PubMed ID

  • 22632606
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Additional Document Info

start page

  • 4215

end page

  • 4222

volume

  • 18

issue

  • 27

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