6/19/18 Direct Oral Anticoagulants A Comprehensive History and Current Developments BCSLS Telehealth Seminar, Vancouver, BC June 26, 2018 Terence M. Litavec B.Sc., MLT(CSMLS), SHCM(ASCP)HCM,MLTCM,HTLCM(ASCP)QIHCCM Acknowledgements: 2017-2018 KGH Student Interns British Columbia College of New Institute of Caldonia, Technology, Burnaby Prince George Stefani Guidi, MLT Soraya Hadjirul, MLT Henry Lu, MLT Neelam Lilly, MLT Jenna Zhang, MLT Alix Savoy, MLT Dawny Tabilangan, MLT Overview and Objectives (A Work In Progress) Provide background information about the classification and function of DOAC’s Outline the various subtypes of DOAC’s listing their similarities and differences List the brief histories and the most current advances in the field of DOAC drug development Discuss the abnormalities in routine screening coagulation assays for patients taking DOAC’s Describe the laboratory assays used to measure the level of DOAC medication in plasma samples 1 6/19/18 Direct Oral Anticoagulants (DOAC) A new class of drugs to treat and prevent thrombosis related to: Acute Coronary Syndrome (ACS), Atrial Fibrillation (AF), Cerebrovascular Accident (CVA), Myocardial Infarction (MI), Joint Replacement, etc. Can be given as an immediate treatment for an acute crisis, or as a long-term anticoagulant regiment Can be given as alternatives to traditional “clot- busting” medications in patients who have developed sensitivities to Heparin (HIT antibody formation) or Warfarin (Coumadin-related limb gangrene due to Protein C inhibition) Do not require scheduled monitoring, but they typically cause abnormalities in coag screening assays (PT, aPTT) Alternate Names For DOAC’s NOAC = Novel Oral Anticoagulants, label initially applied to Dabigatran (Praxada) when it was introduced to the US market in 2010 Since 2010, additional medications with similar mechanisms of action have been developed which render the description “novel” no longer applicable Novel - (adj.) of a new kind, different from anything seen or known before, having no precedent; (syn.) new, original, first-ever, unique, uncommon, unheard-of NOAC = Non-vitamin K Oral Anticoagulants, was introduced by the American College of Chest Physicians (Feb. 2016) to keep the same acronym, but it has been criticized as being too vague and cumbersome NOAC can be mistaken as “NO AntiCoagulants” Alternate Names For DOAC’s TSOAC = Target-Specific Oral Anticoagulant ODI = Oral Direct Inhibitor SODA = Specific Oral Direct Anticoagulant “DOAC seems to be a very reasonable term moving forward that should be embraced by clinicians to describe these new oral anticoagulants and oral anticoagulants with similar direct mechanisms that haven’t yet been released.” Source: Kane, S., NOAC, DOAC, or TSOAC: What Should We Call Novel Oral Anticoagulants? Sept.19, 2016 www.pharmacytimes.com 2 6/19/18 United States Food and Drug Administration (USFDA) Drug Development Process After a drug is manufactured and tested using animal models, human testing is carried out in 3 Clinical Trial Phase Studies (Source: www.fda.gov) Phase I – Safety and Dosage on a group of healthy volunteers – Several Months Phase II – Efficacy and Side Effects on a group of patients with a disease or condition – Up to 2 Years Phase III – Efficacy and Monitoring of Adverse Reactions on a group of volunteers with a disease or condition – 1 to 4 Years – 25-30% of all drugs tested will be approved for further review Biological Half-Life Definition: The time required for the body to eliminate half of an administered dose of any substance by regular physiological processes The plasma drug level falls at a logarithmic rate that is dependent upon factors such as: the nature and composition of the drug, accumulation of the drug in tissues, activity of the drug metabolites, and interactions between the drug and its target receptor within the body Examples: Oxaliplatin (Colorectal Cancer medication) = 14 minutes Bedaquiline (Tuberculosis medication) = 5½ months Drug Levels Displaying 1-Hour Half-Life www.slideshare.net 3 6/19/18 Subcategories of DOAC’s Direct Thrombin Inhibitors – Bind to one or more active sites or exosites on both free and fibrin-bound thrombin (Factor IIa) thereby preventing the conversion of soluble fibrinogen (Factor I) into a fibrin monomer; also display an anti-platelet effect by reducing the thrombin- mediated activation of platelets Factor Xa Inhibitors – Bind directly to both free and clot- bound Factor Xa resulting in an interruption of both the intrinsic and extrinsic pathways of the cascade sequence without requiring cofactors such as ATIII (Sources: Nisio, M., et al. N. Engl. J. Med. 2005;353:1028-1040, Samama, M. Thromb. Res. 2011 Jun;127(6):497-504) Direct Thrombin Inhibitors Univalent – Bind only to the active site of thrombin: Dabigatran, Argatroban, Inogatran, Efegatran, Melagatran (Ximelagatran) Bivalent – Bind to both the active site and exosite 1 of thrombin: Hirudin and derivatives Lepirudin, Desirudin, Bivalirudin Allosteric Inhibitors – New class of medications currently under investigation which inhibit thrombin using a variety of approaches: Ichorcumab (parenteral thrombin inhibitor), BMS-986177 (oral FXIa inhibitor), BAY- 1213790 Xisomab and Aximab (parenteral FXIa inhibitors), several FXIIa monoclonal antibodies are under investigation 4 6/19/18 Inogatran - Parenteral Entered Phase I Clinical Trials in 1995 Half-life = 1 hour, aPTT and TCT were doubled Discontinued by AstraZeneca during Phase II Clinical Trials due to a lack of efficacy compared to heparin for preventing ischemic events in patients with unstable coronary artery disease (CAD) (Sources: Teger-Nilsson, A. et al. J. Amer. Coll. Cardiol. Feb 1995, Volume 25, Issue 2, Supp. 1, p 117A-118A; TRIM-Thrombin Inhibition in Myocardial Ischaemia Study Group. Euro. Heart J. 1997(18):1416-1425) Efegatran - Parenteral Tested in a Phase II Clinical Trial from May 1995 to June 1996 in cardiovascular patients with unstable angina, and MI patients undergoing thrombolytic therapy Half-life in humans not published, caused a dose- dependent prolongation of aPTT and TCT Analysis of Phase II data demonstrated that Efegatran “exhibited equivalent efficacy” to Heparin and was discontinued by Eli Lilly Pharmaceuticals (Sources: The PRIME Investigators, Am. Heart J. 2002;143:95-105; Shuman, R. and Gesellchen, P. Integration of Pharmaceutical Discovery and Development Ch. 4 pp. 57-80, Springer, Boston, MA. ISBN – 978-0-306-47384-5) 5 6/19/18 Argatroban (Acova) - Parenteral Licensed in 2000 and USFDA approved in 2002 for use in percutaneous coronary interventions (angioplasty) in patients who have HIT or are at risk for developing HIT Half-life = 50 minutes, metabolized by the liver Monitored using the aPTT, therapeutic range is 1.5 to 3x the initial baseline value, but can not exceed 100 sec In healthy patients (without HIT), anticoagulation was 4x faster with Argatroban than with UFH and produced more predictable dose-related increases of the activated clotting time (ACT) and the aPTT (Sources: Bambrah, R., et al. Ther. Adv. Chronic Dis. 2013 Nov;4(6):302-304, Swan, S., et al. Pharmacotherapy 2000 July;20(7):756-770) Melagatran (Ximelagatran) Ximelagatran was the first oral direct thrombin inhibitor developed and approved for Clinical Trials in Dec. 2003 Ximelagatran is a pro-drug which is converted by the liver to the active agent Melagatran During clinical trials, the results were comparable to Warfarin and LMWH for VTE prophylaxis However, 6%-12% of patients developed elevated liver enzymes subsequent to severe hepatotoxicity leading to its withdrawal by AstraZeneca in 2006 (Sources: Eriksson, B. I. Thromb. Haemost. 2002 Feb;87(2):231-7. Brighton, T. A. Med. J. Aust. 2004 Oct 18;181(8):432-7) Dabigatran (Praxada) USFDA approved in October 2010 for treatment and prophylaxis of DVT and PE as well as prophylaxis of VTE and stroke in patients with atrial fibrillation Half-life = 12-17 hours, eliminated by the kidney (80%) Recommended as an alternative to Warfarin in 2011 with no need for frequent monitoring due to its stable hematologic response and short half-life In the therapeutic range (27-411 ng/mL), the PT, aPTT, and ACT were not affected, the TCT and dilute TCT displayed good linear correlation with lower doses only (Sources: Ganetsky, M., et al. J. Med. Toxicol. 2011 Dec;7(4):281-287, Hawes, E., et al. J. Thromb. Haemost. 2013 Aug;11(8):1493-1502) 6 6/19/18 Idarucizumab (Praxabind) A monoclonal antibody fragment developed by Boehringer Ingelheim Pharmaceuticals for the reversal of Dabigatran (Praxada) Displays a binding affinity with Dabigatran that is 350x stronger than Dabigatran’s binding affinity with thrombin ensuring rapid and complete reversal of Dabigatran within minutes after IV infusion USFDA approved in 2015 (Source: Pollack, C., et al. N. Engl. J. Med. 2015 Aug;373:511-520) Hirudin and Derivatives Hirudin is produced by the salivary glands of the European Medicinal Leech Hirudo medicinalis, first isolated and studied in 1884 by John Berry Haycraft Native (Unmodified) Hirudin is not recommended for acute coronary syndrome due to significantly higher incidence of bleeding compared to Heparin Native Hirudin is not given as a medication, but it has been evaluated as a universal anticoagulant in blood collection tubes for hematology, clinical chemistry, and blood bank testing (Source: Menssen, HD, et al. Clin. Chem. Lab Med. 2001 Dec;39(12):1267-1277) All Hirudin derivatives must be given