Effect of erythromycin on the pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran and its active form melagatran

Dorani, Hassan; Schützer, Kajs-Marie; Sarich, Troy C.; Wall, Ulrika; Ohlsson, Lis; Eriksson, Ulf G.

doi:10.1016/j.clpt.2003.11.295

Cited by 8 publications

(9 citation statements)

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“…Ximelagatran does not undergo hepatic metabolism via the cytochrome P450 system in the liver; hence, ximelagatran and its active metabolite, melagatran, are less likely to interact with drugs cleared hepatically. The only interaction that has been discovered thus far is a doubling of the rate of absorption when given concurrently with erythromycin [103], but this has not led to an increase in side effects or bleeding diathesis. Dosage reduction is necessary in patients with renal insufficiency [101].…”

Section: Direct Thrombin Inhibitorsmentioning

confidence: 98%

Recent Developments in Antithrombotic Therapy: Will Sodium Warfarin Be a Drug of the Past?

Desai¹,

Massad²,

DiDomenico³

et al. 2006

PRC

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Warfarin and heparin have formed the mainstay in the prophylaxis of deep vein thrombosis (DVT), stroke prevention in atrial fibrillation, and treatment of thromboembolic disease (TED). However, these choices are hampered by difficult administration, interactions with other medications, side effect profile, and limited indications for treatment. Anti-factor Xa (anti-Xa) inhibitors have already entered the drug market with the drug Fondaparinux being the first anti-Xa inhibitor to be approved for use in the U.S. by the Food and Drug Administration (FDA), and other drugs such as idraparinux being currently in development. A new class of medications, known as direct thrombin inhibitors (DTI), includes the parental agents lepirudin, argatroban and bivalirudin which have been approved by the FDA and the oral agents ximelagatran, melagatran and dabigatran. The latter three drugs which are oral DTIs may soon replace warfarin and heparin as the preferred medications for DVT prophylaxis and for reducing the relative risk of stroke. These drugs do not rely on blocking serine proteases nor do they require a co-factor (antithrombin III) like unfractionated heparin (UFH) or low molecular weight heparin (LMWH). DTIs are rapid in onset, easy to administer, do not interact with other medications or foods, have limited side effects, and can be administered in a fixed dose. The DTI ximelagatran has already been approved in several European and Asian countries, and over a dozen randomized clinical trials have been conducted demonstrating its performance to be on par with warfarin. However, approval by the FDA in the U.S. remains pending in view of reported incidences of elevations in hepatic enzymes that are currently under evaluation. This review examines the role of DTIs in the prevention and treatment of TED and the recent patents reported in the literature.

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Section: Direct Thrombin Inhibitorsmentioning

confidence: 98%

Recent Developments in Antithrombotic Therapy: Will Sodium Warfarin Be a Drug of the Past?

Desai¹,

Massad²,

DiDomenico³

et al. 2006

PRC

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“…A pharmacokinetic interaction between ximelagatran and erythromycin was associated with only a minor change in activated partial-thromboplastin time (38). Although ximelagatran metabolism appears independent of the P 450 enzyme system (35), the mechanism of interaction with erythromycin is under investigation.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Ximelagatran: Oral direct thrombin inhibition as anticoagulant therapy in atrial fibrillation

Halperin¹

2005

Journal of the American College of Cardiology

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Atrial fibrillation (AF) causes 50,000 to 100,000 ischemic strokes annually in the U.S., most of which could be prevented by oral anticoagulant treatment of the highest-risk patients. The greatest barrier to such treatment is the narrow therapeutic index of the vitamin K antagonists ([VKAs]: warfarin and related coumarin derivatives), the only oral anticoagulant agents currently available. Safe and effective treatment with the VKAs requires careful monitoring, because they interact with many other drugs and foods, and their anticoagulant action is unpredictable. Besides vitamin K, candidate targets for anticoagulant therapy include thrombin, a key prothrombotic mediator. Ximelagatran, the oral direct thrombin inhibitor at the most advanced stage of clinical development, is rapidly absorbed and bioconverted to its active moiety, melagatran-a potent, competitive inhibitor of both free and clot-bound thrombin. Two large clinical trials have demonstrated that fixed-dose oral ximelagatran, 36 mg twice daily, administered without coagulation monitoring, prevents stroke and systemic embolic events in patients with nonvalvular AF as effectively as well-controlled, adjusted-dose warfarin (international normalized ratio 2.0 to 3.0). The overall risk of bleeding was lower with ximelagatran than warfarin, although differences in rates of major hemorrhage were not statistically significant. Elevation of serum alanine aminotransferase levels above 3x the upper limit of normal occurred in approximately 6% of ximelagatran-treated patients but typically returned toward pretreatment levels without associated symptoms. In terms of preventing thromboembolism without hemorrhage, ximelagatran may have a more favorable benefit:risk profile than warfarin for patients with AF.

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“…Gender and ethnicity seems not to be related with ximelagatran activity [36], while renal function is important for its excretion [37]. Some drug-to-drug interactions with ximelagatran have been noted [38][39][40][41][42][43]. Although ximelagatran will most likely never be introduced in clinical practice, a short account of the evidence regarding its safety and efficacy will be given, since these data may pertain to some of the issues of discussion regarding newer thrombin inhibitors which have found their way to market, namely dabigatran.…”

Section: Ximelagatranmentioning

confidence: 99%

Prevention and Treatment of Venous Thromboembolism and Pulmonary Embolism: The Role of Novel Oral Anticoagulants

Deftereos

Hatzis²,

Kossyvakis³

et al. 2012

CCP

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Venous thromboembolism, encompassing deep vein thrombosis and pulmonary embolism, is the third most common cause of vascular death after myocardial infarction and stroke. Clinicians are often summoned to make challenging decisions for the prevention and treatment of high risk patients with an unpredicted outcome, often relying on data that are less than definitive. During the last decades, heparins (unfractionated and low molecular weight heparins) as well as vitamin K antagonists, such as warfarin, and indirect Xa inhibitors, such as fontaparinux, are the cornerstone for the prevention and treatment of patients with venous thromboembolism. However, the traditionally used anticoagulants have several drawbacks that may limit their efficacy and use in every day clinical practise. The newly developed oral anticoagulants, belonging to the categories of direct thrombin inhibitors (DTIs) and direct Xa inhibitors, have emerged as promising agents with remarkable efficacy, concentrating many parameters of an ideal anticoagulant. Rivaroxaban, dabigatran and apixaban are the most studied agents, while a plethora of others are investigated in clinical trials of different phases and are expected to reach the market in the following years. The purpose of this review is to summarize the so far acquired knowledge on these agents, to report briefly some of their pharmacodynamic and pharmacokinetic properties and to focus on their role in the treatment and prevention of venous thromboembolism.

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Effect of erythromycin on the pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran and its active form melagatran

Cited by 8 publications

References 0 publications

Recent Developments in Antithrombotic Therapy: Will Sodium Warfarin Be a Drug of the Past?

Recent Developments in Antithrombotic Therapy: Will Sodium Warfarin Be a Drug of the Past?

Ximelagatran: Oral direct thrombin inhibition as anticoagulant therapy in atrial fibrillation

Prevention and Treatment of Venous Thromboembolism and Pulmonary Embolism: The Role of Novel Oral Anticoagulants

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