Development of Rivaroxaban - Essay Example

DEVELOPMENT OF RIVAROXABAN By Class: Professor: University: City: Date: Introduction The first anticoagulant was developed in 1914. However, the drug and subsequent development suffered from several inherent weaknesses. For example, the conventional method of administering them was through injections; therefore, frequent nurses visit were necessary for outpatients who could not inject themselves. Fortunately, Bayer initiated the development of anticoagulant that could be taken orally by the patient in 1998 (Kubitza, D., Perzborn, E. and Berkowitz, S. 2013, 2). The Drug was termed as Xarelto and was first presented to the U.S. pharmaceutical market in the year 2007. However, Rivaroxaban was approved for medical use in the country in the year 2011. According to the patent regulation, the patent for the drug is set to expire in the year 2020. Moreover, Janssen Pharmaceutical markets the drug in the U.S. It is imperative to note that it is the first direct factor Xa inhibitor to be developed for oral administration. The effects of the drug last for approximately 8- 12 hours. Moreover, Factor Xa does not reset to its normal factor until the expiry of 24 hours. Consequently, Rivaroxaban is normally taken as a single daily dose. Owing to its efficacy it is imperative to explore the development stages of the drug from its discovery to its endorsement. Drug discovery The drug is used as a cure and prevents thromboembolic disorders. The traditional anticoagulant drugs had the principal merit as their ability to target multiple coagulation factors. However, they suffered from the problem of consistent medical monitoring and adjustment of the dosage. The cause of the problem was the variation of the pharmacodynamics response due to the interaction between the two active components: heparin and vitamin K. Previously studies had discovered that both factor X, in particular in its activated state factor Xa influence blood clotting by influencing the production of thrombin (Kubitza, D., Becka, M., Voith, B., Zuehlsdorf, M. and Wensing, G., 2005, 415). Previous researchers were aware of the fact that factor Xa was responsible for catalyzing prothrombinase and activate it into thrombin. Therefore, the primary targets of the anticoagulant rivaroxaban were factor X, Xa and thrombin. In the preclinical stage of the drug development process, the researchers made two significant discoveries concerning rivaroxaban. One, the drug had a potential to treat by binding to the factor Xa in the prothrombinase thus preventing the formation of blood clots. Next, the research team also discovered that the drug could heal thrombosis in the veins and the arteries in animal trials. After the success of the preclinical stage, the developers progressed to the clinical stage. The primary aim of the clinical stage was to determine the pharmacological impact of the drug in the humans in order to test its feasibility. The researchers found out that the drug had the effect of prolonging the time of prothrombin activity and inhibiting the production of thrombin. The predictability of the results in the human coupled with similar effects with those of the existing anticoagulant ensured that rivaroxaban would progress into the expensive and complicated phase of drug development. Coagulation disorders have been studied in relation to other maladies that they may cause such as malignancy. A recent study demonstrated that cancer and other forms of tumors affect the homeostasis system of the body. Consequently, a tumor had the potential to activate the coagulation factors. On the other hand, the blood clots contribute to the growth and the development of cancer and tumors. Therefore the researchers successfully proved that the use of direct anticoagulant factors could help to improve the palliative care for cancer patients by preventing or treating incidences of hemorrhage and thromboembolic disorders. Therefore, the developers of the drug were motivated to solve the health risks that are associated with the coagulant factor mainly factor Xa. Target Validation & Discovery of Lead Compound As early as 1989 researchers had succeeded in demonstrating that Factor Xa that occurred naturally were capable of targeting the factor Xa and causing significant anticoagulation effect (Dunwiddie, C., Thornberry, N.A., Bull, H., Sardana, M., Friedman, P.A., Jacobs, J.W. and Simpson, E., 1989, 16696). A case in point the studies by Dunwiddle et al. attested to this fact. The researchers were also able to develop an effective synthetic factor Xa inhibitor by the year 2002 as indicated by the findings of Turpie et al. Further development resulted in manufacturing of selective inhibitors of the factor Xa (Turpie, A., Bauer, K., Eriksson, B., and Lassen, M. 2002, 1835). Consequently, it was possible to prevent further generation of thrombin without affecting the operation of the existing one prior to the drug being administered. Most of the trials at this stage focused on rabbits. The researchers compare the efficacy of the injected trial drug and the one administered orally. They concluded that the injected drug was more effective in reducing the symptoms observed in the rabbits. However, increasing the dosage of the oral drug by approximately three times was equally affected as the injected one. Consequently, the efficacy of the oral version of the drug was determined that led to the researchers concentrating on a drug that could be taken by the patient orally. Rivaroxaban was not only the first effective drug to be developed to harness the findings of the previous researches. In addition, it was also the first drug to gain approval of the relevant regulating body. A with any drug development the researchers demonstrated the desired pharmacodynamics effects of the drug during the preclinical trials. Moreover, in the clinical stage, the researchers succeeded in showing that the drug was capable of preventing and treating thromboembolic disorders. During the third phase, Bayern Company was able to reaffirm the results of observed in the clinical stage by testing the drug on a large scale since it had been proven to be promising in the clinical trials which were of at a smaller scale. After the drug successfully passed all the requirements of the third phase the drug was approved for clinical uses. The researchers employed the technique of High-throughput on approximately 200,000 compounds. A few of these compounds were successful in selectively inhibiting the cleavage of the human factor Xa. Through this technique, it was possible to select the compounds that would optimize the performance of the drug being developed. Rivaroxaban was identified as the lead substrate that would increase the potency of the drug due to its superior antithrombotic activities and oral method of injection. The mode of action of the drug is to act as a direct and selective competitive inhibitor of the factor Xa. Unlike the past treatment drugs such as the low molecular weight heparins and fondaparinux that acted by targeting the antithrombin, the success of rivaroxaban was determined by its ability to inhibit prothrombinase that it directly targeted( Hillarp, A., Baghaei, F., Fagerberg Blixter, I., Gustafsson, K., Stigendal, L., STEN‐LINDER, M., Strandberg, K., and Lindahl, T., 2011, 134). In addition, the trial drug was able to enhance the desired pharmacological effect by increasing the period for the commencement of the thrombin generation process. Drug Development Stage The aim of phase I studies of the drug development process aimed at determining the efficacy of the drugs in human. In particular, the researcher purposed at demonstrating that the drug could be useful in preventing and curing thromboembolic disorders. The specific findings of this stage included evaluating the effectiveness of a single daily dose and multiple doses (Stampfuss, J., Kubitza, D., Becka, M. and Mueck, W., 2013, 550). The researchers found out that the single dose was the most effective since it achieved approximately 75% inhibition of the factor Xa. In addition, the studies revealed that a single 80mg dose was sufficient to produce the desired effect in the test sample that included young volunteer males. The optimum functioning of the drug commenced from 45 minutes and 1 hour and lasted up to 4 hours. However, the drug was still inhibition effect of the drug lasted for up to 24 hours. The researcher extended their study to explore the impact of administering multiple dosages to the sample. The researchers administered 5 or 30 mg dose for three times in a way, however; there was no significant improvement in the efficacy of the drug in the young male subjects (Einstein Investigators, 2010, 2500). As a result in the year 2008, there was conclusive evidence that the most efficient dosage was a single daily one. In the second phase the performance of the drug was compared with the most effective one in the market (enoxaparin) in preventing and curing venous thrombolism (Eriksson, B., Borris, L., Friedman, R., Haas, S., Huisman, M., Kakkar, A., Bandel, T., Beckmann, H., Muehlhofer, E., Misselwitz, F. and Geerts, W., 2008, 2267). The patient that was used to test the efficacy of the degrees had recently undergone replacement surgery either in their knee or in the hip (Eriksson, B., Borris, L., Dahl, O., Haas, S., Huisman, M., Kakkar, A., Misselwitz, F., Muehlhofer, E. and Kälebo, P., 2007, 687). Again the researcher used a single dose and one that was administered twice daily. In both cases, the researchers identified that the observed pharmacodynamics effects were as predicted. In addition, the drug was also tested for the prevention of acute and proximal deep vein thrombosis (Agnelli, G., Gallus, A., Goldhaber, S.Z., Haas, S., Huisman, M.V., Hull, R.D., Kakkar, A. Misselwitz, F. and Schellong, S., 2007, 182). Owing to its desirable method of administration and stability the drug was further tested in the final third phase. The third phase was principally concerned with determining the clinical efficacy of the drug. In order to achieve this goal more patients who were at risk of developing thromboembolic disorders were put under study to evaluate the effect of the drugs (Turpie, A., Fisher, W., Bauer, K., Kwong, L., Irwin, M., Kälebo, P., Misselwitz, F. and Gent, M., 2005, 2480). The number of the patient was significantly increased in order to achieve more comprehensive results. In addition, they suffered from a wider array of risk factors that included recent hip and knee replacement surgeries, pulmonary embolism and the treatment of deep vein thrombosis Conclusion The development of the drug rivaroxaban lasted for approximately a decade. However, the initial discovery that led to the development of the drug was made in 1989 when researchers discovered that natural antithrombin factors that could bind to the factor Xa were effective in preventing and treating thromboembolic disorders. Subsequently, synthetic antithrombin that specifically targeted the factor Xa that was responsible for activating the clotting factors were developed. Next, animal trials were conducted to help determine the pharmacological effects during the preclinical trials. In the first phase of the drug development process, it was discovered that the drug was effective in animals thus could be applied to humans. In the second phase, the efficacy of the drug was tested on a group of healthy individuals that revealed that it could be applied in humans. In the final third stage, the researchers were able to demonstrate that the drug was capable of treating a broad array of thromboembolic disorders. References Agnelli, G., Gallus, A., Goldhaber, S.Z., Haas, S., Huisman, M.V., Hull, R.D., Kakkar, A.K., Misselwitz, F. and Schellong, S., 2007. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939). Circulation, 116(2), pp.180-187. Dunwiddie, C., Thornberry, N.A., Bull, H.G., Sardana, M., Friedman, P.A., Jacobs, J.W. and Simpson, E., 1989. Antistasin, a leech-derived inhibitor of factor Xa. Kinetic analysis of enzyme inhibition and identification of the reactive site. Journal of Biological Chemistry, 264(28), pp.16694-16699. Einstein Investigators, 2010. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med, 2010(363), pp.2499-2510. Eriksson, B.I., Borris, L.C., Dahl, O.E., Haas, S., Huisman, M.V., Kakkar, A.K., Misselwitz, F., Muehlhofer, E. and Kälebo, P., 2007. Dose-escalation study of rivaroxaban (BAY 59-7939)–an oral, direct Factor Xa inhibitor–for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thrombosis research, 120(5), pp.685-693. Eriksson, B.I., Borris, L.C., Friedman, R.J., Haas, S., Huisman, M.V., Kakkar, A.K., Bandel, T.J., Beckmann, H., Muehlhofer, E., Misselwitz, F. and Geerts, W., 2008. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. New England Journal of Medicine, 358(26), pp.2765-2775. Hillarp, A., Baghaei, F., Fagerberg Blixter, I., Gustafsson, K.M., Stigendal, L., STEN‐LINDER, M., Strandberg, K. and Lindahl, T.L., 2011. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. Journal of Thrombosis and Haemostasis, 9(1), pp.133-139. Kubitza, D., Becka, M., Voith, B., Zuehlsdorf, M. and Wensing, G., 2005. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59‐7939, an oral, direct factor Xa inhibitor. Clinical Pharmacology & Therapeutics, 78(4), pp.412-421. Kubitza, D., Perzborn, E. and Berkowitz, S.D., 2013. The discovery of rivaroxaban: translating preclinical assessments into clinical practice. Frontiers in pharmacology, 4. Stampfuss, J., Kubitza, D., Becka, M. and Mueck, W., 2013. The effect of food on the absorption and pharmacokinetics of rivaroxaban. International journal of clinical pharmacology and therapeutics, 51(7), pp.549-561. Turpie, A.G., Bauer, K.A., Eriksson, B.I. and Lassen, M.R., 2002. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Archives of internal medicine, 162(16), pp.1833-1840. Turpie, A.G.G., Fisher, W.D., Bauer, K.A., Kwong, L.M., Irwin, M.W., Kälebo, P., Misselwitz, F. and Gent, M., 2005. BAY 59‐7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose‐ranging study. Journal of Thrombosis and Haemostasis, 3(11), pp.2479-2486. Read More