Original ArticleSafety and Functional Pharmacokinetic Profile of APAC, a Novel Intravascular Antiplatelet and AnticoagulantCraige, Simon MSc*; Jouppila, Annukka MSc†,‡; Humphries, Bob BSc§; Lassila, Riitta MD, PhD‡,¶,‖ Author Information *EdGe Toxicology Consulting Limited, Stratford Upon Avon, United Kingdom; †Clinical Research Institute HUCH, Helsinki, Finland; ‡Research Program Unit in Systems Oncology, Faculty of Medicine, Unit of Coagulation Disorders, University of Helsinki, Helsinki, Finland; §VisionRealisation Ltd, Shepshed, United Kingdom; ¶Comprehensive Cancer Center, Department of Hematology, Unit of Coagulation Disorders, Helsinki University Hospital, Helsinki, Finland; and ‖Aplagon Ltd, Helsinki, Finland. Correspondence: Simon Craige, MSc, EdGe Toxicology Consulting Limited, 57 Ely St, Stratford Upon Avon, WARKS, CV37 6LN, United Kingdom (e-mail: [email protected]). All funding for the development of APAC and preparation of this article was undertaken by Aplagon Ltd. S. Craige and B. Humphries act as consultants for Aplagon Ltd. A. Jouppila received research funding from Aplagon Ltd. R. Lassila is the CSO and a stockholder of Aplagon Ltd. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org). Journal of Cardiovascular Pharmacology 78(3):p 453-462, September 2021. | DOI: 10.1097/FJC.0000000000001080 Buy SDC Metrics 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. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.