Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
INTRODUCTION Thrombosis is the major cause of morbidity and mortality. There are many advances in the medical therapy for the treatment of thromboembolic events but the morbidity and mortality rates are still high[1]. So there is a need for therapy which may be more effective in this condition. Thrombin plays an important role in the generation of a thrombus. Because thrombin is the last serine protease in the blood coagulation cascade that causes conversion of fibrinogen to fibrin clot. One approach is the inhibition of thrombin activity by direct thrombin inhibitors[2]. While another approach is the inhibition of thrombin production by blocking the proteases in the blood coagulation cascade, such as factor Xa(FXa). Experiments show that FXa inhibitors have a low risk of bleeding as compared to thrombin inhibitors in animals[3,4]. Hence the inhibition of FXa appears to be important for anticoagulant therapy[5,6]. Apixaban, a direct FXa inhibitor, is a newly developed compound which is highly potent and has more than 30000 fold selectivity than other coagulation proteases[7]. It inhibits both free and cell bound factor Xa and activated prothrombinase[8,9]. It is relatively bio available with a half life of 12 hour and it has also low potential for drug-drug interactions[10,11]. So the desirable pharmacological profile makes apixaban an improved treatment option than other anticoagulants. Apixaban is currently evaluated for multiple indications, including venous thromboembolism (VTE) prophylaxis, VTE treatment and acute coronary syndrome (ACS)[12]. It has been evaluated for prevention of venous thromboembolic events in patients after knee replacement surgery[13] and was also efficacious in acute symptomatic deep vein thrombosis (DVT)[14]. DISCOVERY OF APIXABAN In 1990 the DuPont scientists made efforts in the development of inhibitors of glycoprotein IIb/IIIa receptor. By the mid-1990 scientists at DuPont had observed that there are similarities between the platelet glycoprotein IIb/IIIa peptide sequence Arg-Gly-Asp and the prothrombin substrate FXa sequence, Glu-Gly-Arg. By using molecular modelling and structure-based design, FXa inhibitor containing benzamidine with enhanced potency was developed[15,16]. Thrombin is the key enzyme responsible for the fibrin clot formation and platelet activation. It plays an important role in the formation of thrombi in arteries or veins which may lead to thrombotic disease. Thus the thrombin inhibition either directly or via blockade of other proteases that are involved in thrombin generation such as FXa has been investigated as a novel means to treat thrombotic disease. There are some hypotheses that inhibition of FXa may be valuable for effective and safe antithrombotic therapy. In the process of blood coagulation the generation of one molecule of FXa can lead to the activation of hundreds of thrombin molecules[17]. So the inhibition of FXa may reduce fibrin clot formation than the direct inhibition of thrombin activity. Experimental evidence from animal studies suggests that the antithrombotic efficacy of FXa inhibitors is accompanied by a lower risk of bleeding when compared with thrombin inhibitors[18,19]. Apixaban is a direct, highly selective and reversible inhibitor of FXa, with a rapid onset of action with relatively wide therapeutic index and few food and drug interactions. So there is no need for frequent coagulation monitoring and dose adjustment and the pharmacokinetic and pharmacodynamic profile of apixaban also allows fixed oral dosing. CHEMISTRY Apixaban is a potent, selective, and orally bio available FXa inhibitor containing the novel, neutral, phenyl piperidinone P4 group. The chemical name of apixaban is described as 1-(4methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7 tetrahydro-1H-pyrazolo[3,4- c]pyridine-3-carboxamid[20]. The molecular formula for apixaban is C25H25N5O4 and molecular weight is 459.5. PRECLINICAL STUDIES A number of studies have evaluated the efficacy and safety of apixaban in animals. Wong et al. reported that minimum or moderate effective doses of apixaban enhanced the antithrombotic effect of aspirin and clopidogrel without increasing bleeding time in a rabbit model of arterial thrombosis[21,22]. It has also been reported that apixaban tend to improve the efficacies of antiplatelet therapies, aspirin alone or aspirin plus clopidogrel[23,24]. Studies were conducted in rabbit models of electrically induced carotid artery thrombosis and cuticle bleeding time. Apixaban 0.3 mg/kg/h or aspirin 1 mg/kg/h were infused intravenous continuously before artery injury or cuticle bleed. Clopidogrel at 3 mg/kg was given orally once daily for three days. These drugs can reduce formation of arterial thrombosis without excessive increases in bleeding time in rabbits[25]. The pharmacokinetic parameters of apixaban in rabbits after oral and IV administration are shown in Table 1[26].The plasma concentration of apixaban was rapidly declined after IV administration. The systemic clearance was 2.55 l/h/kg which is high but the half life was short about 0.6 h. After oral administration plasma apixaban exposure was low, with an absolute oral bioavailability of 3%. After IV administration about 24.8% and 62.4% of apixaban was excreted in the urine and feces respectively in 48 hrs in rabbits. While after oral administration, about 1.8% and 54.3% was excreted in the urine and feces respectively[26]. Apixaban has a low bioavailability and a short systemic clearance in rabbits while the rats, dogs and chimpanzees have greater oral bioavailability, much lower clearance rates and a low volume of distribution[27,28]. It is also interesting that the half life of apixaban in rabbit model after oral dosing is relatively longer than after IV administration. The clotting time was also prolonged by apixaban in a concentration-dependent manner. Wong et al. have demonstrated that apixaban was effective for the prevention of venous and arterial thrombosis in rabbits[29]. Fourteen different inactive metabolites of apixaban have been identified[30]. From which O-Demethyl-apixaban was the most important metabolite that is primarily formed via CYP3A4 and undergoes subsequent sulphation to O-Demethyl-apixaban sulphate[31]. CLINICAL STUDIES Pharmacokinetics of apixaban There were many clinical trials completed and many are still continuing regarding the use of apixaban as an anticoagulant in different conditions. Apixaban has a 50% bioavailability and peak levels are achieved within 3 hours and the plasma half-life is 8 to 14 hours as shown in Table 2[32]. Metabolism of apixaban primarily involves CYP3A4 and sulfotransferase. Potent inhibitors of CYP3A4, such as ketoconozole can increase the drug levels. About 25% of the drug is excreted via the kidneys and 55% is excreted in the feces[33]. Pharmacokinetic analyses demonstrate rapid absorption of apixaban after oral administration in healthy male subjects. In the metabolism of apixaban there are several metabolites and the most important is O-demethyl apixaban sulfate. The metabolic pathways for apixaban include O-demethylation, hydroxylation, and sulfation of hydroxylated O-demethyl apixaban. The O-demethyl apixaban sulfate is present in the human faeces which show that it is stable in the gastrointestinal tract during its excretion[34]. After an oral dose of 20 mg of apixaban, 66–72% of the compound is found in the plasma[35]. Food and weight does not have any effect on the absorption of apixaban. The accumulation of drug was also not reported. There was no significant difference on absorption by difference in the age or gender as shown in Table 2[36]. Apixaban can be used in different condition as an anticoagulant like prevention of stroke in patients with atrial fibrillation, venous thromboembolism (VTE) prevention, for secondary prevention in acute coronary syndrome or to prevent the thrombosis in patients with metastatic cancer[12]. Stroke in Atrial Fibrillation Atrial fibrillation (AF) causes about 75,000 cases of ischemic stroke per year in the United States. There are several risk factors for stroke including age greater than 75 years, hypertension, diabetes and smoking[37]. AF causes stroke by thrombus formation in the left atrium with embolism to the brain[38]. Apixaban can be used for prevention of stroke in patients with atrial fibrillation. The ARISTOTLE study was double-blind study including about 18,000 patients with AF from more than 1,000 centres in about 40 countries. The study drug was apixaban 5 mg BD and warfarin 2 mg was used as a control for the reduction of stroke in atrial fibrillation. The primary efficacy outcome is the time to first occurrence of stroke or systemic embolism and the primary safety endpoint is time to first occurrence of confirmed major bleeding. The study will determine whether apixaban is superior to warfarin in preventing stroke and systemic embolism, whether it reduces the combined rate of stroke, systemic embolism, and death and whether it impacts bleeding or not[39]. This study is ongoing but not recruiting new participants. AVERROES was a double blind and parallel design study. About 5000 patients were enrolled in the study. The study is ongoing but not recruiting new participants. It compares apixaban 5 mg twice daily with acetylsalicylic acid 81 to 324 mg once daily for the prevention of stroke or systemic embolism in patients with AF and in the patients who have failed or are unsuitable for vitamin K antagonist treatment. The primary efficacy outcome is stroke or systemic embolism and the primary safety outcome is major bleeding[40]. Apixaban users had a significantly lower risk of stroke and systemic embolic events without increase in bleeding as compared to patients treated with aspirin. Stuart JC et al have conducted the study at 522 centres in 36 countries. About 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable were randomly assigned to the study. They received either apixaban 5 mg twice daily or aspirin 81 to 324 mg per day. The primary efficacy outcome was the occurrence of stroke or systemic embolism. The primary safety outcome was the occurrence of major bleeding. The stroke or systemic embolism was reported in 51 patients assigned to apixaban and in 113 patients assigned to aspirin. The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group. There were 11 cases of intracranial bleeding with apixaban and 13 with aspirin. It was concluded that in patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial haemorrhage[41]. Orthopaedic Replacement Surgery The venous thromboembolism including deep venous thrombosis and pulmonary embolism is life- threatening condition after the major orthopaedic surgery like total knee replacement (TKR) or total hip replacement (THR). The prophylactic treatments available include unfractionated heparin, low-molecular-weight heparins, and vitamin K antagonists[42]. The thromboprophylaxis with low-molecular weight heparins can reduces the venous thromboembolism, but the treatment is costly and daily injections are required on the other hand vitamin K antagonists can also be used for long-term management but regular monitoring is needed, it also interacts with food and is also associated with increased occurrence of bleeding[43]. These limitations show that a standard prophylactic drug is required which can reduce the frequency of venous thromboembolism without causing bleeding and other complications in postoperative patients. The APROPOS study compared apixaban vs. enoxaparin or warfarin for VTE prevention after total knee replacement. It was a randomized, double-blind, phase II study in which about 1217 patients were enrolled. The dose of apixaban was 5–20 mg per day while enoxaparin 30mg twice daily for 12 days began 12–24 h after skin wound closure and warfarin was used in a dose to maintain international normalization ratio (INR) 1.8 to 3.0. Apixaban showed similar efficacy as compared with enoxaparin and warfarin for reducing the VTE. The incidence of major bleeding was 0.0–3.3% for the apixaban doses as compared to no incidence of bleeding in enoxaparin and warfarin groups[44]. The incidence of alanine aminotransferase (ALT) elevation was lower in the apixaban treatment groups than the enoxaparin group. Several phase III apixaban studies for VTE prevention after orthopaedic surgery has been initiated. There were three ADVANCE studies conducted which determined the efficacy and safety of apixaban 2.5 mg twice daily compared with enoxaparin in patients who had undergone the major orthopaedic surgery[45]. The first phase III orthopedic prophylaxis trial named ADVANCE-1has been completed which randomized 3195 patients, in double-blind fashion. Patients received either apixaban 2.5 mg orally twice a day or enoxaparin 30 mg subcutaneously every 12 hours. Both the treatments were started 12 to 24 hours after surgery. All patients underwent venography after 2 weeks. The primary efficacy outcome was VTE and all cause mortality and the primary safety outcome was major bleeding[46].The primary event occurred in 8.99% of patients in apixaban group and 8.85% in the enoxaparin group. Major bleeding was seen in 0.7% patients of apixaban group and 1.4% for enoxaparin group[47]. ADVANCE-2 was the second phase III study among the three trials of efficacy and safety of apixaban for prevention of venous thromboembolism after elective total knee or hip replacement[48]. It was a multicenter, double-blinded, randomized phase III study comparing apixaban 2.5 mg BD for thromboprophylaxis after total knee replacement. As a control enoxaparin 40 mg subcutaneously daily was used. About 3221 patient were enrolled in the study[47].The primary efficacy outcome was deep vein thrombosis, non-fatal pulmonary embolism and all-cause death. The primary safety outcome was bleeding[48].The deep vein thrombosis, non-fatal pulmonary embolism and death were reported in 15.1% in apixaban patients and 24.4% in enoxaparin patients. Clinically relevant bleeding occurred in 3.5% and 4.8% patients treated with apixaban and enoxaparin, respectively. These data indicates that apixaban can prevent the thromboembolic events with decreased bleeding as compared to enoxaparin[47].This study fails to show the superiority against venous thromboembolism, which is widely accepted as the efficacy endpoint. The reports of adverse events were similar in each study group and four patients died during study from which one was from enoxaparin group and three were from apixaban group[48]. ADVANCE-3 which was the third phase III study comparing apixaban to enoxaparin for VTE prevention in the patients undergoing elective total hip replacement surgery. It was a parallel group, double blind study involving about 5000 patients from whom 2708 patients randomized to apixaban 2.5 mg twice daily for 35 days given 12 to 24 hours following surgery and 2699 randomized to enoxaparin 40mg once daily for 35 days started the evening before surgery. The primary efficacy endpoint was DVT, pulmonary embolism and death and the primary safety outcome was occurrence of bleeding. The DVT, pulmonary embolism and death was observed in 1.4% patients receiving apixaban and 3.9% in patients receiving enoxaparin. The occurrence of bleeding was 4.8% and 5.0% respectively in apixaban group and enoxaparin group while the incidence of non fatal pulmonary embolism was 0.1% and 0.2% in apixaban group and enoxaparin group respectively[47]. For the secondary treatment of VTE the Botticelli DVT (Deep Vein Thrombosis) doseranging study was conducted which was the first phase II study to evaluate the safety and efficacy of apixaban for treatment post symptomatic DVT[49]. It was a multicenter, double-blinded study involving 520 patients with acute symptomatic proximal DVT. They were randomized either to different doses of apixaban 5 mg BD, 10 mg BD or 20 mg daily or the low molecular weight heparin (LMWH) followed by vitamin K antagonist (VKA) with target INR 2.0–3.0. The primary efficacy outcome was the symptomatic recurrent VTE. The primary safety outcome was clinically relevant bleeding. The symptomatic recurrent VTE occurred in 4.7% of apixaban patients and 4.2% of LMWH/VKA patients. Bleeding occurred in 7.3% and 7.9% of patients in the apixaban and LMWH/VKA groups respectively. During study it was noted that symptomatic recurrent VTE decreased in the higher doses of the apixaban, it was concluded that all 3 doses of apixaban showed similar efficacy and safety. So the lowest dosage regimen, 5 mg BD has been used in follow-up phase III trials[47]. The AMPLIFY trial was the follow-up trial to the Botticelli DVT trial. It was a double blind study involving randomization of 4816 patients to either apixaban 10 mg BD for 7 days followed by 5 mg BD for 6 months versus enoxaparin 1mg/kg twice daily until INR≥2 followed by warfarin for an INR between 2-4, once daily for 6 months[50].The primary endpoint was venous thromboembolic recurrence or death and the primary safety outcome was bleeding. This study is still ongoing. The AMPLIFY-EXT study is investigating apixaban at 2.5 mg or 5 mg BD for 12 months compared with placebo following symptomatic VTE treatment[50]. It is a phase III multicenter, double-blind, randomized study involving about 2430 patients. The primary efficacy outcome is venous thromboembolic recurrence or death and primary safety outcome is bleeding. This study is ongoing. Apixaban is also being evaluated for thromboprophylaxis in acutely ill medical patients during and following hospitalization in ADOPT trial. It is a phase III, multi-centre, double-blind, randomized study involving about 6524 patients. The patients receive either apixaban 2.5mg twice daily for 30 days or enoxaparin 40mg subcutaneously once daily for 6-14 days. The primary efficacy endpoint is VTE and VTE-related death and secondary outcome is all causes of death, major bleeding, and clinically relevant non-major bleeding. The study is still ongoing and currently recruiting participants[51]. Cancer The cancer patients have a high risk for thrombosis such as VTE. The cancer-associated thrombosis is the major cause of morbidity and mortality. The incidence of VTE increases from 0.1% in the general population to 0.5% in patients with cancer annually[52].The rate of occurrence of VTE varies depending on the types of patients. Chemotherapy increases the risk of VTE by 6-fold and the cancer patients have an estimated annual incidence of VTE of about 1 in 200[53].Generally anticoagulants are used to prevent and treat the thrombosis but current anticoagulants are problematic in cancer patients. Parenteral anticoagulants like heparin or low-molecular heparin require daily subcutaneous injection and oral anticoagulant such as warfarin requires coagulation monitoring and dose adjustments. Apixaban has been evaluated in small phase II study involving about 125 patients with advance or metastatic cancer receiving chemotherapy. The patients received either apixaban 5 mg daily for 12 week or placebo. The study result shows that apixaban is well tolerated, with very few thrombotic and bleeding events but to demonstrate the efficacy larger studies are required[54]. Acute Coronary Syndrome In case of acute coronary syndrome (ACS), either ST-elevation or non–ST-elevation, the patients remain at increased risk for recurrent ischemic events[55]. A number of therapeutic options are available for ACS. The anticoagulants are one of them. Oral anticoagulants have been shown to prevent recurrent ischemia after ACS[56]. Apixaban is a newer oral anticoagulant which may be used to prevent the reoccurrence of ACS. The APPRAISES-I study was conducted to evaluate the effect of apixaban for prevention of acute ischemia. It was a phase II, double-blind, placebo-controlled study involving 1715 patients with recent ST-elevation or non–ST-elevation acute coronary syndrome. The patients were either randomized to apixaban or placebo. The four different doses of apixaban were used. 317 patients received 2.5 mg twice daily, 318 patients received 10 mg once daily, 248 patients received 10 mg twice daily and 611 patients received 20 mg once daily. 221 patients received placebo for 6 months. All patients received aspirin and about 76% received clopidogrel. The primary efficacy outcome was the severe recurrent ischemia, cardiovascular death, myocardial infarction or recurrent stroke. The primary safety outcome was major or clinically significant bleeding[57]. Apixaban 2.5 mg twice daily and 10 mg once daily resulted in a dose-dependent increase in bleeding as compared to placebo. Apixaban 2.5 mg twice daily and 10 mg once daily resulted in lower rates of ischemic events compared with placebo. The two higher-doses of apixaban were discontinued because of excess total bleeding. The patients who took aspirin plus clopidogrel had more bleeding and less reduction in ischemic events compared to those taking aspirin alone. Overall event rates and the benefits of apixaban were greater among patients not taking clopidogrel. So the safety and efficacy of apixaban may vary depending on concomitant antiplatelet therapy. This trial was unable to detect a statistically significant difference in the rates in the composite efficacy endpoint of severe recurrent ischemia, nonfatal heart attack and cardiovascular death[57]. Richard CB et al have studied the effect of apixaban on D-dimer, prothrombin fragment 1+2 (F1+2), C- reactive protein, fibrinogen and other inflammatory markers. The D-dimer and prothrombin fragment 1+2 level was elevated in most of patients at baseline as shown in Table 3. Both of this decreased in 3 week in all groups, but the decrease was more with apixaban than with placebo. The prothrombin fragment 1+2 was suppressed more rapidly by 10 mg QD than 2.5 mg BID. The C- reactive protein and fibrinogen levels declined in all patients. So it was concluded that apixaban reduced D-dimer and prothrombin fragment 1+2 levels more rapidly toward normal values as compared to placebo[58]. CONCLUSION The apixaban is a factor Xa inhibitor which acts as an anticoagulant. Several trials have been done for investigating its anticoagulant activity in different conditions. Apixaban has been shown to decrease the risk of stroke events without increase in bleeding when compared with the patients taking aspirin. In patients whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without increasing the risk of bleeding in atrial fibrillation. Apixaban also shows superiority for VTE prevention in the patients undergoing total hip replacement surgery as compared to enoxaparin. More bleeding has been reported at higher doses of apixaban than at lower doses during treatment of post symptomatic deep vein thrombosis. Apixaban is also effective to prevent VTE in patients with metastatic cancer receiving chemotherapy. Apixaban has been also shown to reduce the ischemic events in acute coronary syndrome but the risk of bleeding was more. There are many conditions where apixaban can be a better alternative than other anticoagulants. Its efficacy profile is acceptable but further evaluation is necessary to prove its safety profile. REFERENCES 1. Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T et al., Heart disease and stroke statistics – 2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2006, 113, 85-151. 2. Gustafsson D., Oral direct thrombin inhibitors in clinical development. J Intern Med 2003, 254, 322-334. 3. Leadley RJ., Coagulation factor Xa inhibition:biological background and rationale. Curr Top Med Chem 2001, 1, 151-160. 4. Wong PC, Crain EJ, Watson CA, Zaspel AM, Wright MR, Lam PY et al., Nonpeptide factor Xa inhibitors III: effects of DPC423, an orally-active pyrazole antithrombotic agent,on arterial thrombosis in rabbits. J Pharmacol Exp Ther 2002, 303, 993-1000. 5. Quan ML, Wexler RR., The design and synthesis of noncovalent factor Xa inhibitors. Curr Top Med Chem 2001, 1, 137-149. 6. Wong PC, Pinto DJ, Knabb RM., Nonpeptide factor Xa inhibitors: DPC423, a highly potent and orally bioavailable pyrazole antithrombotic agent. Cardiovasc Drug Rev 2002, 20, 137-152. 7. Pinto DJ, Orwat MJ, Koch S, Rossi KA, Alexander RS, Smallwood A et al., Discovery of 1-(4methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent,selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem 2007, 50, 5339–5356. 8. Luettgen JM., In vitro evaluation of apixaban, a novel, potent, selective and orally bioavailable factor Xa inhibitor. Blood 2006, 108, 4130. 9. Jiang X., Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro. Thromb Haemost 2009, 101, 780-782. 10. Raghavan N., Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009, 37, 74-81. 11. He K., Preclinical pharmacokinetic and metabolism of apixaban, a potent and selective factor Xa inhibitor. Blood 2006, 108, 910. 12. Christopher RJ, Richard CB., Apixaban: an emerging oral factor Xa inhibitor. J Thromb Thrombolysis 2010, 29, 141-146. 13. Lassen MR, Davidson BL, Gallus A, Pineo G, Ansell J, Deitchman D., The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007, 5, 2368-2375. 14. Buller HR., A dose finding study of the oral direct factor Xa inhibitor apixaban in the treatment of patients with acute symptomatic deep vein thrombosis–on behalf of the Botticelli investigators. J Thromb Haemost 2007, 5, 3. 15. Quan ML, Ellis CD, Liauw AY, Alexander RS, Knabb RM, Lam G., Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. J Med Chem 1999, 42, 2760-2773. 16. Wong PC, Quan ML, Crain EJ, Watson CA, Wexler RR, Knabb RM., Nonpeptide factor Xa inhibitors: I. Studies with SF303 and SK549, a new class of potent antithrombotics. J Pharmacol Exp Ther 2000, 292, 351-357. 17. Mann KG, Butenas S, Brummel K., The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol 2003, 23, 17-25. 18. Harker LA, Hanson SR, Kelly AB., Antithrombotic benefits and hemorrhagic risks of direct thrombin antagonists. Thromb Haemost 1995, 74, 464-472. 19. Wong PC, Crain EJ, Watson CA, Xin B., Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared with the thrombin inhibitor dabigatran in rabbits. J Thromb Haemost 2009, 7, 1313-1320. 20. James RC, Tianan F, Donald JP, Wei H, Zilun H, Xiang JJ et al., Structure–activity relationships of anthranilamide-based factor Xa inhibitors containing piperidinone and pyridinone P4 moieties. Bioorg Med Chem Lett 2008, 18, 2845-2849. 21. Wong PC, Crain EJ, Watson CA, Zaspel AM, Wright MR, Lam PY., Nonpeptide factor Xa inhibitors III: effects of DPC423, an orally-active pyrazole antithrombotic agent, on arterial thrombosis in rabbits. J Pharmacol Exp Ther 2002, 303, 993-1000. 22. Wong PC, Watson CA, Crain EJ., Arterial antithrombotic and bleeding time effects of apixaban, a direct factor Xa inhibitor, in combination with antiplatelet therapy in rabbits. J Thromb Haemost 2008, 6, 1736-1741. 23. Alexander JH, Becker RC, Bhatt DL, Cools F, Crea F, Dellborg M et al., APPRAISE Steering Committee and Investigators. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009, 119, 2877-2885. 24. Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F et al., ATLAS ACSTIMI 46 study group. Rivaroxaban versus placebo in patients with acute coronary syndromes:a randomised, double-blind, phase II trial. Lancet 2009, 374, 29-38. 25. Wong PC, Crain EJ, Xin B, Wexler RR, Lam PY, Pinto DJ et al., Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008, 6, 820-829. 26. Donglu Z, Kan H, Nirmala R, Lifei W, Earl JC, Bing He et al., Metabolism, pharmacokinetics and pharmacodynamics of the factor Xa inhibitor apixaban in rabbits. J Thromb Thrombolysis 2010, 29, 70-80. 27. Davies B, Morris T., Physiological parameters in laboratory animals and humans. Pharma Res 1993, 10, 1093-1095. 28. He K, He B, Grace JE, Zhang D, Pinto DJ, Luettgen JM et al., Preclinical pharmacokinetics and metabolism of apixaban, a potent and selective factor Xa inhibitor. Blood 2006, 108, 910. 29. Wong PC, Crain EJ, Xin B, Wexler RR, Lam PY, Pinto DJ et al., Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost 2008, 6, 820-829. 30. Zhang D, He K, Raghavan N., Comparative Metabolism of C-14 Labeled Apixaban in Mice, Rats, Rabbits, Dogs, and Humans. Drug Metab Dispos 2009, 37, 1738-1748. 31. Wang L, Raghavan N, He K., Sulfation of o-demethyl apixaban: enzyme identification and species comparison. Drug Metab Dispos 2009, 37, 802-808. 32. Eriksson BI, Quinlan DJ, Weitz JI., Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet 2009, 48, 122. 33. Raghavan N, Frost CE, Yu Z, He K, Zhang H, Humphreys WG., Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009, 37, 74-81. 34. Nirmala R, Charles EF, Zhigang Y, Kan H, Haiying Z, Humphreys WG et al., Apixaban Metabolism and Pharmacokinetics after Oral Administration to Humans. Drug Metabolism And Disposition 2008, 37, 74-81. 35. Meyer MS, Grigoris TG., Newer anticoagulants in 2009. J Thromb Thrombolysis 2010, 29, 92104. 36. Alexander GG., New oral anticoagulants in atrial fibrillation. Eur Heart J 2007, 29, 155-165. 37. Sacco RL, Adams R, Albers G., Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack. Stroke 2006, 37, 577-617. 38. Stoddard MF, Dawkins PR, Prince CR, Ammash NM., Left atrial appendage thrombus is not uncommon in patients with acute atrial fibrillation and a recent embolic event: a transesophageal echocardiographic study. J Am Coll Cardiol 1995, 25, 452-59. 39. Renato DL, John HA, Sana MA, Jack A, Raphael D, Donald E et al., Apixaban for Reduction In Stroke and Other ThromboemboLic Events in Atrial Fibrillation (ARISTOTLE) trial: Design and rationale. Am Heart J 2010, 159, 331-340. 40. John WE, Martin D, Salim Y, Rafael D, Greg F, Robert H et al., Rationale and design of AVERROES: Apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J 2010, 159, 348-353. 41. Stuart JC, John E, Campbell J, Hanschristoph D, Robert H, Sergey G et al., Apixaban in Patients with Atrial Fibrillation. N Engl J Med 2011, 432, 1-12. 42. Geerts WH, Bergqvist D, Pineo GF., Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2008, 133, 381-453. 43. Fareed J, Hoppensteadt DA, Fareed D., Survival of heparins, oral anticoagulants, and aspirin after the year 2010. Semin Thromb Hemost 2008, 34, 58-73. 44. Lassen MR, Davidson BL, Gallus A, Pineo G, Ansell J, Deitchman D., A phase II randomized, double-blind, eight-arm, parallel-group,dose-response study of apixaban, a new oral Factor Xa inhibitor for the prevention of deep vein thrombosis in knee replacement surgery on behalf of the apixaban investigators. Blood 2006, 108, 574. 45. Alexander GG., New oral anticoagulants in atrial fibrillation. Eur Heart J 2007, 29, 155-165. 46. David G, Edward L, Mark AC., The new oral anticoagulants. Blood 2010, 115, 15-20. 47. Christopher RJ, Richard CB., Apixaban: an emerging oral factor Xa inhibitor. J Thromb Thrombolysis 2010, 29, 141-146. 48. Michael RL, Gary ER, Alexander G, Graham P, Dalei C, Philip H., Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial Lancet 2010, 375, 807-815. 49. Buller H., Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008, 6, 1313-1318. 50. Yoshitake S., Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). Biochemistry 1985, 24, 3736-3750. 51. Jeffrey IW., Factor Xa and thrombin as targets for new oral anticoagulants. Thrombosis Research 2011, 127, 5-12. 52. Silverstein, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ., Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998, 158, 585-593. 53. Heit JA, Silverstein, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ., Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000, 160, 809-815. 54. Levine MN, Deitchman D, Julian J., A randomized phase II trial of a new anticoagulant, apixaban, in metastatic cancer. J Clin Oncol 2009, 27, 14. 55. Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Hochman JS et al., 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction. J Am Coll Cardiol 2008, 51, 210-247. 56. Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR., Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med 2005, 143, 241-250. 57. Alexander JH, Becker RC, Bhatt DL, Cools F, Crea F, Dellborg M et al., Results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) Trial Apixaban, an Oral, Direct, Selective Factor Xa Inhibitor, in Combination With Antiplatelet Therapy After Acute Coronary Syndrome. Circulation 2009, 119, 2877-2885. 58. Richard CB, John HA, YuChen B, Honqqui Y, Jessie W, Lars W, Robert AH., Effect of apixaban on coagulation activity biomarkers following acute coronary syndrome: lessons from the appraise trial. J Am Coll Cardiol 2010, 55, 102. TABLE 1: PHARMACOKINETIC PARAMETERS OF APIXABAN IN RABBIT AFTER A SINGLE IV OR ORAL DOSE Sr no. 1. 2. 3. 4. 5. 6. 7. 8. Pharmacokinetic parameter Dose (mg/kg) Tmax (h) Cmax (µM) AUC0-t (µM h) AUCInf (µM h) Vdss (l/kg) Clearance (l/h/kg) Absolute bioavailability (%) IV (mean ± SD) 2.5 NA 10.25 ± 3.07 2.36 ± 0.98 2.37 ± 0.99 0.88 ± 0.22 2.55 ± 0.91 NA Oral (mean ± SD) 10 1.00 ± 0.87 0.03 ± 0.01 0.12 ± 0.03 0.25 ± 0.06 NA NA 3.00 ± 1.66 TABLE 2: PHARMACOKINETICS AND PHARMACODYNAMIC PARAMETERS OF APIXABAN IN HUMAN Sr no. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Pharmacokinetic parameter Pro drug Bioavailability Tmax Reversible Half-life Mode of excretion Accumulation Food Age effect Weight effect Gender effect Apixaban No 50% 3h Yes 8–15 h 70% in faeces and 25% renal Not reported Not reported Not reported Not reported Not reported TABLE 3: EFFECT OF APIXABAN ON DIFFERENT BIO-MARKERS Sr. No. 1. 2. 3. 4. Reference Time Biomarker interval duration D-dimer (ng/ml) F1+2 (pmol/L) C-reactive protein (mg/L) Fibrinogen (mg/dl) 0-251 87-325 0.068-8.2 206-382 Apixaban Placebo Pre dose Week 3 317 2.5 mg BID 325 10 mg QD 325 10 mg BID 314 20 mg QD 321 258 206 185 176 185 Week 26 207 172 163 - - Pre dose 299 309 307 328 332 Week 3 267 201 161 167 157 Week 26 246 191 184 - - Pre dose Week 3 23.1 22.7 21.7 25.5 21.7 4.45 3.81 4.21 4.34 4.41 Week 26 3.65 3.07 3.52 - - Pre dose 478 472 458 470 471 Week 3 372 367 372 359 375 Week 26 331 325 337 - -