Preclinical safety and pharmacokinetic profile of 3K3A-APC, a novel, modified activated protein C for ischemic stroke.
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.
IND Directions, LLC, Catharpin, VA 20143, USA.
Patricia D
PD
Williams
Berislav V
BV
Zlokovic
John H
JH
Griffin
Kent E
KE
Pryor
Thomas P
TP
Davis
D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D002545:Brain Ischemia / Q000188:drug therapy / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D006207:Half-Life; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011486:Protein C / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D013045:Species Specificity; D020521:Stroke / Q000188:drug therapy / Q000503:physiopathology
D000925:Anticoagulants; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated