Patricia D. Williams, Berislav V. Zlokovic, John H. Griffin, Kent E. Pryor and Thomas P. Davis Pages 4215 - 4222 ( 8 )
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 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.
Neuroprotection, anticoagulant activity, toxicology, pharmacokinetics, Activated protein C (APC), protease, ischemic injury, sepsis, clinical trials, clotting assays.
Professor of Medical Pharmacology and Program in Physiology and Neurosciences, University of Arizona College of Medicine, Life Sciences North Room 542-AHSC, 1501 N. Campbell Avenue, P.O. Box 245050, Tucson, Arizona. 85724-5050, USA.