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

Patricia D. Williams, Berislav V. Zlokovic, John H. Griffin, Kent E. Pryor, Thomas P Davis

Research output: Contribution to journalArticle

32 Citations (Scopus)

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 toxicokine ics.Dose-related increases in plasma total 3K3A-APC were observed in mice and monkeys with no evidence of accumulation over 14 days. The elimination T1/2 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 1/10thof those showing effects with 3K3A-APC. Based upon the anticoagulant profiles, the risk for APCinduced 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.

Original languageEnglish (US)
Pages (from-to)4215-4222
Number of pages8
JournalCurrent Pharmaceutical Design
Volume18
Issue number27
DOIs
StatePublished - 2012

Fingerprint

Protein C
Pharmacokinetics
Stroke
Safety
Proteins
Haplorhini
Anticoagulants
Clinical Trials
Hemorrhage
Macaca fascicularis
United States Food and Drug Administration
Recombinant Proteins
Toxicology
Endothelium
Sepsis
Peptide Hydrolases

Keywords

  • Anticoagulant activity
  • Neuroprotection
  • Pharmacokinetics
  • Toxicology

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

Preclinical safety and pharmacokinetic profile of 3K3A-APC, a novel, modified activated protein c for ischemic stroke. / Williams, Patricia D.; Zlokovic, Berislav V.; Griffin, John H.; Pryor, Kent E.; Davis, Thomas P.

In: Current Pharmaceutical Design, Vol. 18, No. 27, 2012, p. 4215-4222.

Research output: Contribution to journalArticle

Williams, Patricia D. ; Zlokovic, Berislav V. ; Griffin, John H. ; Pryor, Kent E. ; Davis, Thomas P. / Preclinical safety and pharmacokinetic profile of 3K3A-APC, a novel, modified activated protein c for ischemic stroke. In: Current Pharmaceutical Design. 2012 ; Vol. 18, No. 27. pp. 4215-4222.
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