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Safety and Functional Pharmacokinetic Profile of APAC, a Novel Intravascular Antiplatelet and Anticoagulant.
- Source :
-
Journal of cardiovascular pharmacology [J Cardiovasc Pharmacol] 2021 Sep 01; Vol. 78 (3), pp. 453-462. - Publication Year :
- 2021
-
Abstract
- Abstract: Vascular intervention-induced platelet and coagulation activation is often managed with a combination of antiplatelets and anticoagulants, with evident benefits, but with a risk of systemic bleeding. Antiplatelet and anticoagulant (APAC) is a dual antiplatelet and anticoagulant heparin bioconjugate, which targets vascular injury sites to act as a local antithrombotic. We assessed the nonclinical safety and exposure of intravenously infused APAC in rats and cynomolgus monkeys by using single-day and 14-day repeat dose toxicology and pharmacodynamic markers. Activated partial thromboplastin time (APTT) was used as a functional surrogate of anticoagulant exposure of APAC. Routine clinical in-life observations were followed by clinical pathology and necropsy. The no-observed-adverse-effect level (NOAEL) in rats for the single APAC dose was 20 mg/kg and for the repeated administration was 10 mg/kg/d. Monkeys tolerated a single APAC dose of 10 mg/kg, although the red blood cell count reduced 16%-19% correlating with tissue hemorrhage at vein puncture and affected muscle sites during handling of the animals. However, after 2-week recovery, all clinical signs were normal. The single dose NOAEL exceeded 3 mg/kg. The repeat administration of 3-6 mg/kg/d of APAC was tolerated, but some clinical signs were observed. The NOAEL for repeated dosing was 0.5 mg/kg/d. APAC prolonged APTT dose-dependently in both species, returning to baseline after 1.5 (<10 mg/kg) or essentially by 6 hours also under repetitive dosing. The toxicology profile supports the safety of an intravenous APAC dose of 0.5 mg/kg/d for possible clinical applications. APTT is an acceptable indicator of the immediate systemic anticoagulation effect of APAC.<br /> (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Subjects :
- Animals
Anticoagulants administration & dosage
Anticoagulants toxicity
Dose-Response Relationship, Drug
Female
Heparin administration & dosage
Heparin analogs & derivatives
Heparin toxicity
Infusions, Intravenous
Macaca fascicularis
Male
No-Observed-Adverse-Effect Level
Partial Thromboplastin Time
Platelet Aggregation Inhibitors administration & dosage
Platelet Aggregation Inhibitors toxicity
Prothrombin Time
Rats, Wistar
Rats
Anticoagulants pharmacokinetics
Blood Coagulation drug effects
Heparin pharmacokinetics
Platelet Aggregation Inhibitors pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1533-4023
- Volume :
- 78
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of cardiovascular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 34132685
- Full Text :
- https://doi.org/10.1097/FJC.0000000000001080