ximelagatran (investigational)

Action and Spectrum

Actions and Spectrum: 

Action: 

ximelagatran is a direct thrombin inhibitor. Thrombin is an enzyme involved in the formation of blood clots. By inhibiting thrombin’s activity, ximelagatran helps prevent the formation of new blood clots and reduces the risk of clot-related complications, such as strokes or deep vein thrombosis. 

Spectrum:  

Stroke Prevention in Atrial Fibrillation Patients: Atrial fibrillation is characterized by an irregular heart rhythm. which may result in the development of blood clots within the heart. These clots have the potential to migrate to the brain, potentially leading to a stroke. In certain instances, ximelagatran has been employed as a measure to mitigate this risk. 

Prophylaxis of deep vein thrombosis & pulmonary embolism: ximelagatran may be prescribed to prevent the development of blood clots in high-risk situations, such as after orthopedic surgeries like hip or knee replacements. 

Drug Interaction

Adverse Reaction

Frequency not defined  

 elevations in alanine transaminase (ALT) 

Black Box Warning

Black Box Warning:  

None

Contraindication / Caution

Contraindication/Caution:  

Hypersensitivity to ximelagatran or any of its components: ximelagatran may provoke hypersensitivity reactions in susceptible individuals. Patients with a history of hypersensitivity, allergic reactions, or anaphylaxis to ximelagatran or related compounds should not receive this medication.  

Active Bleeding or High Risk of Bleeding: ximelagatran significantly affects the clotting process by inhibiting thrombin. Consequently, its use is strictly contraindicated in patients with active bleeding, regardless of the site or severity of the bleeding. Furthermore, individuals with an increased risk of bleeding, such as those with active peptic ulcers, recent major surgery, intracranial hemorrhage, or other conditions predisposing to bleeding, should not be administered ximelagatran. 

Severe Hepatic Impairment: The metabolism of ximelagatran primarily occurs in the liver, and severe hepatic impairment can lead to altered drug metabolism and clearance. Therefore its use is contraindicated in such patients. 

Pregnancy and Breastfeeding: ximelagatran’s impact on pregnant or breastfeeding women remains limited in research, and its safety profile for these specific groups has not been adequately established Therefore, ximelagatran should not be used during pregnancy, and lactating women should be advised to discontinue the drug while breastfeeding. 

Concomitant Use with Certain Medications: ximelagatran’s pharmacokinetics and pharmacodynamics can be influenced by co-administration with specific drugs, potentially leading to adverse effects. Concomitant use with strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin) and strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) is contraindicated, as they may alter ximelagatran’s plasma concentrations and efficacy. 

Pregnancy / Lactation

Pregnancy warnings:     

Pregnancy category: N/A 

Lactation: Excreted into human milk is unknown 

Pregnancy Categories:         

Category A: Studies that were well-controlled and met expectations revealed no risk to the fetus in either the first or second trimester. 

Category B: There were a lack of studies on pregnant women and no evidence of risk to the fetus in animal experiments.   

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.   

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category

Pharmacology

Pharmacology:  

ximelagatran is an oral direct thrombin inhibitor in the class of anticoagulant agents. 

Pharmacodynamics:  

ximelagatran exerts its anticoagulant effects by directly inhibiting the activity of thrombin, a key enzyme in the coagulation cascade responsible for converting fibrinogen into fibrin. Thrombin inhibition prevents fibrin formation, disrupting the formation of stable blood clots. Unlike indirect thrombin inhibitors such as heparins, ximelagatran does not require antithrombin III for its action, making it a direct and specific inhibitor of thrombin.  

Pharmacokinetics: 

Absorption 

ximelagatran is rapidly absorbed following oral administration, with a bioavailability of approximately 35%. The drug’s absorption mainly occurs in the small intestine, with peak plasma concentrations observed within 2 to 4 hours after ingestion. 

Distribution 

ximelagatran exhibits moderate affinity for binding to various proteins in human plasma, with its primary targets being albumin and alpha-1 acid glycoprotein. It possesses a considerable volume of distribution, indicating its capability to distribute extensively throughout the body’s tissues. Research has indicated that the drug can cross the blood-brain barrier to a limited degree, implying restricted penetration into the central nervous system. 

Metabolism 

ximelagatran undergoes minimal hepatic metabolism, primarily via hydrolysis to its active metabolite, melagatran. The conversion of ximelagatran to melagatran occurs predominantly in the liver, involving carboxylesterases. Unlike some other anticoagulants, ximelagatran does not undergo cytochrome P450-mediated metabolism, reducing the risk of drug-drug interactions mediated through this pathway. 

Excretion and Elimination 

The excretion of ximelagatran occurs predominantly through the renal route. After metabolism to melagatran, both the parent drug and its metabolite are renally eliminated. Approximately 70% of the administered dose is excreted in the urine, with the majority (approximately 50%) being excreted as unchanged melagatran. Only a small fraction of the dose is excreted via feces. 

The elimination half-life of ximelagatran is relatively short, ranging from 3 to 5 hours in healthy individuals. However, this half-life may be prolonged in patients with impaired renal function, necessitating dosage adjustments in such cases. 

Adminstartion

Administration:  

ximelagatran should be administered orally with water. It can be taken with or without food. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: ximelagatran(investigational) 

Why do we use ximelagatran (investigational)?  

Prevention of Venous Thromboembolism (VTE): ximelagatran(investigational) plays a pivotal role in the prevention of venous thromboembolism in high-risk patients, Individuals who are undergoing significant orthopedic surgeries like hip or knee replacement can benefit from the use of ximelagatran.  

Acute DVT: In the treatment of acute deep vein thrombosis, ximelagatran(investigational) exhibits potent antithrombotic activity by inhibiting thrombin directly. This targeted mechanism of action results in the prevention of thrombus propagation and fosters the gradual dissolution of existing clots. Consequently, ximelagatran has emerged as an efficacious option for the management of DVT. 

Stroke Prevention in Atrial Fibrillation (AF): Individuals who have been diagnosed with non-valvular atrial fibrillation face an increased risk of stroke because of the development of blood clots (thrombi) within the atria. ximelagatran (investigational) ability to antagonize thrombin, a key player in the coagulation cascade, has shown significant promise in preventing embolic events and reducing the risk of stroke in these patients. 

Post-Thrombotic Syndrome (PTS) Management: PTS, a potential complication following deep vein thrombosis, can lead to chronic venous insufficiency and long-term morbidity. ximelagatran’s (investigational)anticoagulant properties, particularly in the early stages of PTS, have been explored as a therapeutic approach to mitigate symptom progression and improve patients’ quality of life. 

Thromboprophylaxis in Medical Patients: Critically ill medical patients, especially those confined to extended bed rest, are at increased risk of developing venous thromboembolism. Studies have evaluated ximelagatran (investigational) as a prophylactic agent in this population, demonstrating its efficacy in reducing the incidence of VTE events and enhancing overall patient outcomes.