Dabigatran Etexilate's Destination - Literature review Example

Review of literature Dabigatran etexilate is a competitive, reversible, direct thrombin inhibitor that is used for preventing strokes in those patients with atrial fibrillation. It is one of the safe and efficacious drugs for preventing thrombosis. Dabigatran etexilate is taken as an oral drug. Dabigatran etexilate is a pro-drug molecule with no anticoagulant activity. The drug is taken orally and reaches the intestine. At intestine, it undergoes esterase enzymatic hydrolysis and spontaneous decomposition and releases n-hexanol, carbon dioxide and ethanol along with the parent compound, dabigatran. It is then absorbed into the blood. This drug is converted into active form by the enzymes at GI tract, blood and liver. Oral bioavailability of the drug is 5% and the half life of the drug is 12 hours. It is eliminated from the body through kidney. There are no dietary restrictions to this drug and their interactions with food and other drugs are very less. Thus it is safe for use as a medicine. (Colman 2006). Figure 1: Structure of Dabigatran Etexilate (Pro drug) (Colman, 2006). It is unionized at the pH of the intestine. The ammonia group present in the molecule is 70% ionized at the intestine pH 6.5. Figure 2: Structure of the active molecule Dabigatran. It is ionized completely and has both positive and negative charges. The prodrug is 95% unionized at intestine pH. On conversion into the active metabolite, the Amidine group is 99.9% ionized, similarly the acid (COOH) group is 99% ionized. The distribution coefficient value of the prodrug is 10 times higher than the drug badigatran. (Rautio 2011). Chemical Name: Ethyl 3 - { [2 - ( { 4- [(Z) - amino ­(hexyl­oxycarbonyl­imino)­methyl]­aniline } methyl) – 1 - methyl­benzimidazole-5-carbonyl]­ pyridin-2-yl­amino}­propano­ate tetrahydrate, C34H41N7O5·4H2O. (Coonolly et al. 2009). Dabigatran contains an ethyl group at the carboxylic acid and a side chain of hexyloxycarbonyl at the amidine. There is a tri substituted benzimidazole derivative with a benzamindine moiety. This moiety forms a salt bridge with the carboxylate of the aspartate enzyme residue Asp 189. It also adds the carboxylic acid. Dabigatran is a polar and charged molecule. This molecule is not available after administration due to its pH range. Dabigatran is formed from two molecules. It is generated with amidinium moiety with a carbamate ester. The carboxylate group binds to the ester group. The two groups are held together by the hydrolytic cleavage. This pro drug has bioavailability of 7%. Dabigatran attaches to thrombin and cleaves the bonds after arg and lys and converts fibrinogen into fibrin. This activates the factors V, VII, VIII, XIII and also the thrombomodulin protein C. (Drug Bank 2012). The studies also indicate that the concentration of the drug should not exceed 400 mg daily. (Smith et al. 2012). The preclinical pharmacokinetic studies have found that dabigatran etexilate metabolizes more efficiently into dabigatran in vitro and in animal models. The pharmacokinetic parameters were analyzed in all the subjects. The rate of drug exposure and the PK profile of dabigatran were performed. The parameters such as peak plasma concentration, half life of the drug, apparent volume of distribution, mean residence time and the plasma concentration – time profile were determined. The selected coagulation parameters analyzed are aPTT assay, PT assay, TT assay, ECT assay, PK/PD correlation, safety assessments and statistical analysis. It was found that dabigatran had a good PK profile for the healthy volunteers on oral administration. Dabigatran had a bi- exponential distribution phase. Half life was measured to be between 14 – 17 hours. (Stangier et al. 2007). The maximum concentration of dabigatran increased with multiple dosing. Stangier et al. (2007) also state that within 12 hours of single dosing, the plasma concentration was found to be less by 25%. The reduction in the maximum plasma concentration became approximately 30% after attaining the steady state concentration. The pharmaco - dynamic factor was found to decrease with the decrease in the plasma concentration. So to maintain the maximum plasma concentration, the drug was administered twice daily. The elimination of dabigatran was up to 80 % through the renal pathway, aPTT, TT and ECT increased with the dose. The aPTT values increased by two to three fold. Similarly, as pointed out by Scott (2011) the INR, TT and ECT values increased with the increase in the plasma concentration of dabigatran. About 6.5 % of dabigatran etexilate is eliminated as such in the through renal pathway. This indicates that oral bioavailability of the drug is very low. It also concludes that dabigatran etexilate is rapidly converted into dabigatran in the plasma and produces an effective and fast anticoagulation. This study by Stangier et al. (2007) concludes that dabigatran is an effective, predictable and reproducible anticoagulant for the competitive inhibition of thrombin. The synthesis of dabigatran is through chemical process only. There are many ways in which the drug is synthesized and one among them is that of Jin–Jin, Shi-yong and Bo-hua (2012). A most efficient and economic synthesis of dabigatran is as follows: 1) 4-(methylamino)-3-nitrobenzoic acid was reacted with ethyl 3-(pyridin-2-ylamino)propanoate to form ethyl 3-[4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido]propanoate with of 2-chloro-1-methylpyridinium iodide (CMPI )as catalyst. 2) Ethyl 3-[4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido]propanoate is further reduced to ethyl 3-[3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido]propanoate. 3) Ethyl 3-[3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido]propanoate was further reacted with 2-(4-cyanophenylamino)acetic acid to form ethyl 3-{2-[(4-cyanophenylamino)methyl]-1-methyl-N-(pyridin-2-yl)-1H-benzoimidazole-5-carboxamido}propanoate. 4) Ethyl 3-{2-[(4-cyanophenylamino)methyl]-1-methyl-N-(pyridin-2-yl)-1H-benzoimidazole-5-carboxamido}propanoate is made to react with hydroxylamine hydrochloride using the catalysts HCOONH4 and Pd/C to form get ethyl 3-{2-[(4-carbamimidoyl-phenylamino)methyl]-1-methyl-N-(pyridin-2-yl)-1H-benzoimidazole-5-carboxamido}propanoate. 5) The last step in the synthesis of this drug is the reaction with with hexyl carbonochloridate to form dabigatran etexilate. (Jin-jin, Shi-yong and Bo-hua, 2012). Dabigatran is metabolized by the esterases and microsomal carboxylesterases. Acylglucoronides are formed through coagulation and this pharmacologically active form undergoes the reaction. There are four possible positional isomers 1-o, 2- o, 3- o and 4-o. (Drug Bank 2012). About 10% of the total plasma dabigatran contains an isomer each. The primary elimination of the drug is through renal pathway at a rate of 100ml/ min of glomerular filtration rate. Fecal excretion was around 6% of the total dose administered to the subjects. (Drug Bank 2012). Some common adverse effects are dyspepsia and gastritis – like symptoms. The lethal dose was found to be 2000mg / kg for rats and 600mg/ kg in dogs and Rhesus monkeys did not have lethal and toxicological effect. (Drug Bank 2012). In the repeat dose studies it was confirmed that dabigatran is well tolerated in the rats and Rhesus monkeys. Mutagenic potential was nil. Dabigatran etexilate is rapidly absorbed in the blood and has a peak plasma concentration within two hours of administration. After reaching the peak plasma concentration, rapid distribution of the drug inside the body takes place. This is followed by elimination and terminal phase. As the half life of the drug is 12 hours, single and multiple administration of the drug is recommended in the patients. (Braber and Robertson 2012). Dabigatran was found to inhibit both free and fibrin bound thrombin enabling effective inhibition of coagulation. This is not possible with warfarin and heparin. Braber and Robertson (2012) further added that the drug is found to interact with quinidine, doxorubicin, Nefazodone, Amiodarone, Carbamazepine, ketoconazole, amiodarone,verampamil and rifampicin. Scott (2011) provided inputs about the peak anticoagulation effect of the drug by stating it is between half an hour to two and half an hour. Dabigatran etexilate is accepted for clinical use in Canada and other countries for the prevention of venous atrial fibrillation. Dabigatran etexilate was studied and compared with enoxaparin and found to have better effects than 40 mg once daily enoxaparin. The noninferiority level was not met for enoxaparin 30 mg dosage level by dabigatran. (Scott 2011). Dabigatran etexilate is used for the treatment of atrial fibrillation. The drug which gets activated into dabigatran by the action of serum esterase acts as potential competitor for thrombin. This drug does not require continuous monitoring. Dabigatran etexilate was used at dose range of 150 mg twice daily and if used as a single dose then 220 mg. (Scott 2011). The use of the drug at these limits was proved to be efficient the results are promising. When dabigatran was compared with warfarin for the treatment of atrial fibrillation, it was found to be very efficient and potent for the treatment. The study conducted by Connolly et al. (2009) also confirmed that 150 mg dose of dabigatran was better for systemic embolism or stroke. The major bleeding was best arrested by dabigatran for a dose concentration of 110 mg. the myocardial infarction was found to be higher for dabigatran dose than warfarin. The best advantage of dabigatran was the twice- daily dose regimen. With a half life of 12 hours and elimination from the kidney between 12 – 17 hours helps to control the coagulation much better than that of warfarin. Similar results were obtained when the drug was tested in the Japan population. Dabigatran was used as a twice daily dose for the prevention of stroke in the patients for atrial fibrillation. The pharmacokinetic justification was given by Clemens et al. (2012). The pharmacokinetic profile developed by Clemens et al. (2012) for once daily dose of 300 mg and twice daily dose of 150 mg showed two fold difference between the peak plasma levels when compared to the single dose regimen of five- fold increase in the plasma level. The simulation results were found to be consistent with the pharmacokinetic data. Thus they conclude that less fluctuation in the plasma levels was found for twice daily regimen and they recommend it for the treatment of atrial fibrillation. Atrial fibrillation was the most common cardiac disturbance that increases with the age, with the people with atrial fibrillations have increased about 66% in the past twenty years. (Escobar, Barrios and Jimenez 2010). Atrial fibrillation is associated with the long term disadvantages such as heart failure, stroke and all –cause mortality. The treatment recommended for atrial fibrillation was antithrombotic therapy. This therapy will prevent thromoboembolism. In the study by Escobar, Barrios and Jimenez (2010) Warfarin or acenocoumarol was used as the anticoagulant for saving thromboembolic patients but the efficacy was very less and not all the patients recovered. The need for a new anticoagulant was investigated. Dabigatran was found to have lower rates of hemorrhage for the atrial fibrillation patients at a dose concentration of 110 mg twice daily. (Escobar, Barrios and Jimenez, 2010). Atrial fibrillation is associated with dreadful cardioembolic complications. For the stroke risk, the patients were treated with warfarin or aspirin based drugs. But warfarin was found to interact with foods, drugs and also creates hemorrhagic conditions. To identify the better drug direct thrombin inhibitors, indirect thrombin inhibitors, factor Xa inhibitors and vitamin K antagonists were tried. So in order to overcome the risks of warfarin, dabigatran is used. Dabigatran at higher concentrations is proved to show better recovery and prevents stroke and systemic embolism. The bleeding risk is similar to that of warfarin. Nonvalvular atrial fibrillation patients received dabigatran for stroke. The drug is also approved by US Food and Drug Administration. The major drawback of dabigatran is that it causes hemorrhage and there is no specific antidote available for the treatment. (Deedwania and Huang 2012). The use of dabigatran etexilate is found to be the cost –effective method for the treatment of stroke and systemic embolism in UK patients for the first line treatment of atrial fibrillation, as pointed in the study by Kansal et al. (2012). To determine the cost effectiveness of dabigatran etexilate, Markov model was used. Warfarin, aspirin and dabigatran etexilate was used for the determination. The patients who were treated with dabigatran etexilate had less ischaemic strokes when compared to warfarin administered patients. (Kansal et al. 2012)When aspirin and dabigatran etexilate were compared, they found larger difference among them. The cost was 98% and 68% higher for warfarin and aspirin based on the cost and the effect in the treatment than dabigatran etexilate. (Kansal et al. 2012). Intracranial haemorrhage and stroke risk was less in the treatment of dabigatran. Many new oral anticoagulants were tested for the patients with atrial fibrillation instead of warfarin. The studies including one done by Miller et al. (2012) and also by Clemens et al. (2012) have found that apixaban, dabigatran and rivaroxaban to have better efficacy and safe than warfarin treatment in patients with atrial fibrillation. The results were published after a year study with controlled trials. (Miller et al. 2012). The patients with the new anticoagulants were found to have better recovery and decreased stroke and systemic embolism. Intracranial bleeding was also very less compared to warfarin. This study thus concludes that new anticoagulant drugs are more effective than warfarin. A switch from enoxaparin to dabigatran was tested for the venous thromboembolism and stroke prevention in the atrial fibrillation patients. Enoxaparin was given subcutaneously for the 3 days at a dose concentration of 40mg, and on the fourth day dabigatran was administered at a concentration of 220 mg. (Clemens et al. 2012). The level of dabigatran in the plasma was measured using high performance liquid chromatography and Mass spectroscopy tandem method. The level of anticoagulation was also measured using the clotting tests such as activated partial thromboplastin time (aPTT), prothrombinase – induced clotting time ( PiCT), ecarin clotting time ( ECT) and diluted thrombin time (dTT). (Clemens et al. 2012). The data suggested that some amount of enoxaparin activity was present in the blood in the analysis. It was concluded from this data that partial thromboplastin was present in the plasma due to the activation of enoxaparin. The tolerability level of the patients was very good with little adverse effects. The PK and PD properties of dabigatran showed that enoxaparin administration did not have much effect on the patients and suggests that dabigatran alone is enough for the atrial fibrillation. (Clemens et al. 2012). Dabigatran etexilate and atorvastin were co administered and the potential impact on the pharmacokinetics and pharmacodynamics was analyzed by Stangier et al. in 2009. Healthy male and female volunteers were chosen for the analysis and they were made to receive dabigatran etexilate for three days at 150mg twice daily dose concentration. (Stangier et al. 2009). Atorvastin was administered from the fourth day to fourteenth day at a dose concentration of 80 mg. It was observed that there was no effect of two drugs on each other. Thus Stangier et al. (2009) concluded that atorvastin can be administered together with dabigatran or alone but together they did not create adverse effects. In addition, in the healthy volunteers, the peak plasma concentration was reached within two hours of administration and it is not metabolized by the cytochrome P450 isoenzymes. (Stangier et al. 2009). Age and gender were found to play a small role in the variations in renal function. When multiple dosing is given, there was no accumulation of the drug found indicating that multiple dosing does not affect the health of the individual. The drug – drug interaction was not found when administered along with atorvastin, diclofenac and digoxin. There was no hepatic impairment in the patients on drug administration. The pharmacodynamic profile indicates of efficient anti coagulation with risk of bleeding. (Stangier 2008). The safe, therapeutic range of dabigatran etexilate for the patients undergoing hip replacement was determined by Eriksson et al. in 2004. In this study, the patients were given dabigatran etexilate at varying concentrations ranging from 12.5 mg to 300 mg twice daily or 150 and 300 mg once daily. (Erikkson et al. 2004).The drug was administered 4- 8 hours after surgery to the patients for 6 – 10 days. The major outcome analyzed was deep vein thrombosis, symptomatic deep vein thrombosis and pulmonary embolism. There was no major bleeding among the group. Only two patients who received the dose concentration of 300 mg twice daily had bleeding at multiple sites. (Erikkson et al. 2004). The renal clearance was also very less and they had prolonged pharmacodynamic parameters. Most of the patients had evaluable venograms.The lowest rate of drug administration had no effect on atrial fibrillation. This concludes that the drug concentration must be optimized further. The use of dabigatran on the healthy elderly subjects was assessed by (Stangier 2008), with the pharmacodynamic and pharmacokinetic profiles were assessed for gender differences. Similarly the effect of pantoprazole administration along with the dabigatran was assessed. An open parallel group study with a 7 day treatment period was designed and the volunteers were analysed. The subjects were administered with or without pantoprazole for 7 days. The subjects received 150mg of dabigatran twice daily for six days and only on the morning of the seventh day. Pantoprazole administration began two days before the treatment and was ended along with dabigatran on the seventh day. The steady state of plasma concentration was achieved in 3 days with the half life of 12 hours. It was found that the co-administration of pantoprazole decreased the bioavailabilty of the drug by 20%. The direct mode of action of the drug in thrombin was observed. (Stangier 2008). The risk of stroke is increased by five times in the patients associated with atrial fibrillation. To reduce the risk of stroke anticoagulation therapy is practiced. Vitamin K antagonists such as warfarin or acenocoumarol were used for the treatment for the past two decades. The use of dabigatran is practiced recently and has proven efficiency for the treatment of atrial fibrillation and reducing the risk of stroke. The use of long term anticoagulation therapy using dabigatran has proved that it is much better than warfarin. The rate of major hemorrhage was lower. The use of 110 mg of dabigatran twice daily is suitable for the treatment. This study also concluded that dabigatran is useful for different group of persons with different clinical conditions. (Barrios and Escobar, 2012). The effect of dabigatran etexilate on the end stage renal disease was investigated for the effect and efficiency by Stangier et al. (2010). The pharmacodynamics and pharmacokinetics of the drug dabigatran etexilate was studied on an open labeled, parallel group study on patients suffering from mild, moderate and severe renal impairment. (Stangier et al. 2010).The initial creatinine clearance value was 50 – 80 ml / min, 30- 50 ml / min and 0 – 30 ml / min in the renal patients respectively. Along with the renal impairment paitents normal healthy volunteers were also chosen for the study. Dabigatran was administered for the patients and the blood and urine samples were collected. The results were collected up to 96 hours after completion of the dosing regimen. The plasma concentration- time curve was found to move from zero to infinity level. Dabigatran concentration was 1.5, 3.2 and 6.3 times higher in the subjects with mild, moderate and severe renal impairment. (Stangier et al. 2010). The patients with renal impairment had 28 hours terminal elimination half life as compared with the atrial fibrillation patients. The drug prolonged the pharmacokinetic changes along with the pharmacodynamics parameters such as activated partial thromboplastin time and ecarin clotting time. The dose was removed through renal dialysis (hemo dialysis). The drug is well tolerated in all the types of patients ranging from mild, moderate and severe renal impairment patients. The renal impairment was increased with exposure to Dabigatran. Dabigatran etexilate is not administered for epidural anesthesia if a permanent catheter was introduced through operation. Even for post operative anesthesia, this drug is not suitable. This study does not recommend the use of dabigatran etexilate as anticoagulant. (Llau 2012). To understand the efficiency and the detrimental effects of dabigatran and other drugs, the CHADS(2), a simple validated score for the analysis of risk for stroke was used. This is recommended for patients who did not receive anticoagulants for atrial fibrillation. CHADS (2) use the sparse data and predict the risk of thrombotic and bleeding complications in the patients receiving the anticoagulant therapy. This was a multinational study of randomized and controlled trial. The patients with the atrial fibrillation were analyzed for the efficiency. The CHADS score was given as 0, 1, 2, and 3. The primary outcome was analyzed to be between 0-1 for stroke and 2.26 for major bleeding, 0.4 for intracranial bleeding and vascular mortality was around 1.65. (Oldgren et al. 2011). The CHADS score increased as the warfarin and dabigatran dosage level increased in the patients. The risks of stroke, intracranial bleeding, major bleeding and vascular and total mortality increased for increase in the dosage level. Stroke or systemic embolism was lower for a dose concentration of 150 mg twice daily and intracrancial bleeding was low for 150mg or 110 mg twice daily than that of warfarin. (Oldgren et al. 2011). Heterogenecity was not significant among the sub groups. They conclude that higher CHADS score was obtained for increased risks of stroke, intracranial bleeding and death in the patients with atrial fibrillation receiving anti coagulants. (Oldgren et al. 2011). For the patients of age less than 75 years, the studies conducted by Eikelboom et al. in 2011, has showed that the risk of bleeding was less for the persons receiving two doses of dabigatran when compared with warfarin for the atrial fibrillation patients. This analysis was a long term randomized analysis with the use of anticoagulation therapy for atrial fibrillation. This trial was also called as RE- LY trial. In this study dabigatran 150 mg and 110 mg twice daily and warfarin were administered to atrial fibrillation patients for the prevention of stroke. (Eikel boom et al. 2011).The bleeding risk was less in the patients of age less than 75 and the risk level increased a bit more for the persons of age greater than 75. This was observed for intra cranial bleeding and not for extra cranial bleeding. Both warfarin and dabigatran had similar results for intra cranial bleeding. This study thus concludes that in younger patients the risk levels were less for dabigatran than warfarin but in older persons of age greater than 75, the risk level was similar. References: Barrios , V and Escobar, C., 2012. New Evidences for old concerns with Oral Anticoagulation in Atrial Fibrillation: Focus on Dabigatran, Expert opinion Pharmacotherpaeutics, Vol. 13, No. 18, pp. 2649 – 61. Barber, P and Robertson, D., 2012. Essentials of pharmacology for Nurses, McGraw- Hill international. Colman, RW., 2006, Hemostasis and Thrombosis: Basic Principles and Clinical Practice, Lippincott Willaims and Wilkins. Connolly, SJ., Ezekowitz, MD., Yusuf, S., Eikelboom, J., Oldgren, J., Parekh, A., Pogue, J., Reilly, PA., Themeles, E., Varrone, J., Wang, S., Alings, M., Xavier, D., Zhu, J., Diaz, R., Lewis, BS., Darius, H., Diener, HC., Joyner, CD., Wallentin, L and RE-LY Steering Committee and Investigators., 2009. Dabigatran versus Warfarin in Patients with Atrial Fibrillation, The New England Journal of Medicine, Vol.17, No. 12, pp. 1139 – 1151. Clemens, A., Haertter, S., Friedman, J., Brueckmann, M., Stangier, J., van Ryn, J and Lehr ,T., 2012. Twice daily dosing of Dabigatran for Stroke Prevention in Atrial Fibrillation: a Pharmacokinetic Justification, Current Medical Research and Opinion, Vol. 28, No. 2, pp. 195-201. Deedwania, P and Huang, GW., 2012. An update on Antithrombic Therapy in Atrial Fibrillation: the Role of Newer and Emergent drugs, Reviews in cardiovascular medicine, Vol.13, No. 2-3, pp. e89 – e104. Drugbank., 2012. Dabigatran etexilate, Drug bank, Open data drug and Drug target databases, [Online] Available from: http://www.drugbank.ca/drugs/DB06695(Accessed on December 4, 2012) Eikelboom, JW., Wallentin, L., Connolly, SJ., Ezekowitz, M., Healey, JS., Oldgren, J., Yang ,S., Alings, M., Kaatz, S., Hohnloser, SH., Diener, HC., Franzosi, MG., Huber, K., Reilly, P., Varrone, J and Yusuf, S., 2011. Risk of bleeding with 2 doses of Dabigatran compared with Warfarin in older and younger Patients with Atrial fibrillation: an Analysis of the Randomized Evaluation of long-term Anticoagulant Therapy, RE-LY Trial, Vol. 123, No. 21, pp. 2363-72 Escobar, C., Barrios, V and Jimenez, D., 2010. Atrial fibrillation and Dabigatran: Has the time come to use New Anticoagulants?, Cardiovascular therapeutics, Vol. 28, No. 5, pp. 295 – 301. Jin-Jin, Z., Shi-yong, F., Bo-hua, Z., 2012. Improved Synthesis of Dabigatran Etexilate, Chinese Journal of Medicinal Chemistry, Vol. 22, No. 3, pp. 204 – 208. Llau, J., 2012. Thromboembolism in Orthopedic Surgery, Springer. Kansal, AR., Sorensen, SV., Gani, R., Robinson, P., Pan, F., Plumb, JM and Cowie, MR., 2012. Cost-effectiveness of Dabigatran Etexilate for the Prevention of Stroke and Systemic Embolism in UK patients with Atrial fibrillation, Heart, Vol. 98, No.7, pp. 573 – 578. Miller, CS., Grandi, SM., Shimony, A., Filion, KB and Eisenberg, MJ., 2012. Meta- Analysis of Efficacy and Safety of new Oral Anticoagulants (Dabigatran, Rivaroxaban, Apixaban) versus Warfarin in Patients with Atrial fibrillation, American Journal of Cardiology, Vol.110, No.3, pp. 453 – 460. Oldgren, J., Alings, M., Darius, H., Diener, HC., Eikelboom, J., Ezekowitz, MD., Kamensky, G., Reilly, PA., Yang, S., Yusuf, S., Wallentin, L., Connolly ,SJ and RE-LY Investigators., 2011. Risks for Stroke, Bleeding, and Death in Patients with Atrial fibrillation receiving Dabigatran or Warfarin in relation to the CHADS2 score: a subgroup analysis of the RE-LY trial, Annals of Internal Medicine, Vol.155, no.10, pp. 660 -667. Rautio, J., 2011. Prodrugs and Targeted Delivery, John Wiley and Sons. Scott, WN., 2011. Insall and Scott Surgery of the knee, Elsevier health sciences. Stangier, J., Rathgen, K., Stahle, H., Gansser, D and Roth, W., 2007. The Pharmacokinetics, Pharmacodynamics and Tolerability of Dabigatran Etexilate, a new Oral direct Thrombin Inhibitor, in Healthy Male Subjects, British Journal of Clinical Pharmacology, Vol.63, No.3, pp. 292 – 303.] Stangier, J., Rathgen, K., Stahle, H and Mazur, D., 2010. Influence of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Oral Dabigatran Etexilate: an open label, parallel – group, single – centre study, Clinical Pharmacokinetics, Vol. 49, No 4, pp. 259 – 268. Stangier, J., Rathgen, K., Stahle, H., Gansser , D and Roth, W., 2009. Co- administration of Dabigatran Etexilate and Atorvastatin: Assessment of potential impact on Pharmacokinetics and Pharmacodynamics, American Journal of Cardiovascular drugs, Vol.9, No.1, pp. 59 – 68. Stangier, J., 2008. Clinical Pharmacokinetics and Pharmacodynamics of the Oral Direct Thrombin inhibitor Dabigatran Etexilate, Clinical pharmacokinetics, Vol.47, No. 5, pp. 285 – 295. Smith, DA., Allerton, C., Kalgutkar, AS., Waterbeemd, H and Walker, DK., 2012. Pharmacokinetics and Metabolism in Drug design, John Wiley and Sons. Read More