In the past 2018, the global drug sales champion was still the macromolecular monoclonal antibody Humira (just short of $20 billion). The Top2 variety is a small molecular drug, but it is no longer lenalidomide. Instead, the anticoagulant FXa inhibitor Apixaban. Apixaban not only surpassed the first drug in the same target, Livarshaban, but also won 2018 global small molecule drug sales NO.1.
Apixaban is a direct factor Xa (FXa) inhibitor used as an anticoagulant to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and to prevent the formation of deep venous thrombosis (deep venous thrombosis, DVT). Apixaban was approved for sale by the European Drug Administration (EMA) on May 18, 2011, subsequently, it was approved by the US Food and Drug Administration (FDA) on December 28, 2012, and approved by the Japanese pharmaceutical and medical device complex (PMDA) on December 25, 2012. Then it was approved by the United States Food and Drug Administration (FDA) on December 28, 2012, and approved by the China Food and Drug Administration (CFDA) on January 22, 2013.
Mechanism of Apixaban
Apixaban can directly inhibit the conversion of prothrombin to thrombin during coagulation cascade blocked by coagulation factor Xa. Factor Xa is a vitamin K-dependent serine protease that occupies the central position in the coagulation waterfall reaction and can be activated by both endogenous and exogenous coagulation pathways. The main catalyst for the transformation of factor Ⅱ (prothrombin) to factor Ⅱa (thrombin), the inhibition of 1mol Xa factor can inhibit the production of 1000mol thrombin. The results show that the inhibition of factor Xa can prolong the dose-dependent effect of lag. Factor Xa contains S1~S4 pocket, catalytic region, cationic cavity, disulfide bridge pocket and so on. S1 and S4 pockets are the main pockets of drug binding. In the process of binding to the active part of Xa, Apixaban has a high selectivity. The dissociation constant Ki combined with Xa is 0.08mol/L (the Ki of Rivaroxaban to Xa is 0.4mol/L), and the Ki of other serine proteases is more than 3mol/L. Therefore, Apixaban has high selectivity and strong effect on Xa. In addition, another characteristic of Apixaban is that it not only can inhibit free Xa and Xa in prothrombin complex, but also inhibit Xa in blood clot, and there is no need for antithrombin III in the process of inhibition. This is different from the effect of heparin anticoagulants such as Fondaparinux sodium.
Approval of indications
For approved indications, in the European Union, The approved indications of Apixaban are the treatment of venous thromboembolism (VTE) for knee joint replacement in adults, stroke and prevention of systemic embolism in adults with non-valvular atrial fibrillation (AF) and prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE). In the United States, the drug is used to reduce the risk of stroke and systemic embolism in adults with non-valvular atrial fibrillation, to prevent deep venous thrombosis that can easily lead to pulmonary embolism in patients undergoing knee and hip replacement, and to treat and prevent VTE. In China, Apixaban is mainly approved for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement. In Japan, it is mainly used to prevent systemic embolism in patients with ischemic stroke and non-valvular atrial fibrillation.
Conclusion
As the confluence of endogenous and exogenous coagulation activation systems, coagulation factor Xa plays an important role in coagulation cascade reaction. Through in-depth research and development, researchers have formed a series of efficient drugs for this target. In recent years, Apixaban has been recognized by doctors and patients for its safer efficacy, and global sales have grown rapidly, gradually become another “super blockbuster drug”.
References
1. Carrier, M., Abou-Nassar, K., Mallick, R., Tagalakis, V., Shivakumar, S., Schattner, A., … & Trinkaus, M. (2019). Apixaban to prevent venous thromboembolism in patients with cancer. New England Journal of Medicine, 380(8), 711-719.
2. Byon, W., Garonzik, S., Boyd, R. A., & Frost, C. E. (2019). Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review. Clinical pharmacokinetics, 1-15.