Effect of the Endothelin‐Receptor Antagonist Bosentan on the Pharmacokinetics and Pharmacodynamics of Warfarin

Weber, Cornelia; Banken, Ludger; Birnboeck, Herbert; Schulz, Rainer

doi:10.1177/00912709922008380

Cited by 76 publications

(47 citation statements)

References 17 publications

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“…Nonetheless, warfarin is a drug with a narrow therapeutic index, so that even slight changes must be considered in the context of clinical relevance. Drug interactions with warfarin have been previously demonstrated for the ERAs bosentan and sitaxsentan [9,[14][15][16]. These interactions have been attributed to alter-ations in the activity of CYP2C9 and CYP3A4 for bosentan and CYP2C9 for sitaxsentan, and these two enzymes are also primarily responsible for metabolism of warfarin.…”

Section: Discussionmentioning

confidence: 97%

The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers

Walker

Mandagere

Dufton

et al. 2009

Brit J Clinical Pharma

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WHAT IS ALRADY KNOWN ABOUT THIS SUBJECT • Warfarin anticoagulation therapy is commonly administered to patients with pulmonary arterial hypertension (PAH) to reduce the risk of thrombosis and embolism. • Ambrisentan is an orally active, propanoic acid‐based endothelin receptor antagonist that is likely to be co‐administered with warfarin to PAH patients. • Concomitant therapies that induce or inhibit warfarin metabolism may alter the systemic exposure of warfarin and significantly alter clotting time, as measured by prothrombin time and International Normalized Ratio, thereby requiring substantial adjustments to warfarin dose. WHAT THIS STUDY ADDS • This study was undertaken in healthy subjects to identify any potential drug interactions between ambrisentan and warfarin. • Multiple doses of ambrisentan had no clinically relevant effects on the pharmacokinetics or pharmacodynamics of warfarin; conversely, a single dose of warfarin had no clinically relevant effects on the steady‐state pharmacokinetics of ambrisentan. • Therefore, co‐administration of ambrisentan with warfarin should not require adjustment of the therapeutically effective dosing regimen for either drug. AIMS Ambrisentan is an oral, propanoic acid‐based endothelin receptor antagonist often co‐administered with warfarin to patients with pulmonary arterial hypertension. The aim of this study was to evaluate the potential for ambrisentan to affect warfarin pharmacokinetics and pharmacodynamics. METHODS In this open‐label cross‐over study, 22 healthy subjects received a single dose of racemic warfarin 25 mg alone and after 8 days of ambrisentan 10 mg once daily. Assessments included exposure (AUC0–last) and maximum plasma concentration (Cmax) for R‐ and S‐warfarin, and International Normalized Ratio maximum observed value (INRmax) and area under the curve (INRAUC(0–last)). The effects of warfarin on ambrisentan steady‐state pharmacokinetics and the safety of ambrisentan/warfarin co‐administration were assessed. Data are presented as geometric mean ratios. RESULTS Ambrisentan had no significant effects on the AUC0–last of R‐warfarin [104.7; 90% confidence interval (CI) 101.7, 107.7) or S‐warfarin (101.6; 90% CI 98.4, 105.0). Similarly, ambrisentan had no significant effects on the Cmax of R‐warfarin (91.6; 90% CI 86.2, 97.4) or S‐warfarin (89.9; 90% CI 84.8, 95.3). Consistent with these observations, little pharmacodynamic change was observed for INRmax (85.3; 90% CI 82.4, 88.2) or INRAUC(0–last) (93.0; 90% CI 90.8, 95.3). In addition, co‐administration of warfarin did not alter ambrisentan steady‐state pharmacokinetics. Adverse events were infrequent, and there were no bleeding adverse events. CONCLUSIONS Multiple doses of ambrisentan had no clinically relevant effects on the pharmacokinetics and pharmacodynamics of a single dose of warfarin. Therefore, significant dose adjustments of either drug are unlikely to be required with co‐administration.

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Section: Discussionmentioning

confidence: 97%

The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers

Walker

Mandagere

Dufton

et al. 2009

Brit J Clinical Pharma

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“…Anaemia was not a problem in the present study population. Anticoagulation with the oral anticoagulant phenprocoumon was altered in the majority of patients, probably due to the induction by bosentan of cytochrome P 450 -dependent metabolism [26,27]. Thus close monitoring of the INR is indispensable in patients undergoing anticoagulation therapy with phenprocoumon as long as they receive bosentan.…”

Section: Discussionmentioning

confidence: 99%

Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids

Hoeper¹,

Taha²,

Bekjarova³

et al. 2003

European Respiratory Journal

182

114

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Primary pulmonary hypertension (PPH) is a life-threatening disease. Nonparenteral prostanoids, i.e. aerosolised iloprost or oral beraprost sodium show beneficial therapeutic effects but are not sufficiently active in all patients with this devastating disease. The purpose of the present study was to determine whether the endothelin-receptor antagonist bosentan is safe and effective in patients with PPH already receiving nonparenteral prostanoids.The effect of bosentan as add-on medication was studied in 20 patients with PPH, who received either inhaled iloprost (n=9) or oral beraprost (n=11) for a median period of 16¡13 months, by means of the 6-min walk test and cardiopulmonary exercise testing.After 3 months of administration of bosentan in addition to prostanoids, the walking distance in the 6-min walk test increased by 58¡43 m. Cardiopulmonary exercise testing revealed an increase in maximal oxygen consumption from 11.0¡2.3 to 13.8¡3.6 mL?kg -1 ?min -1 accompanied by significant improvements in anaerobic threshold, oxygen pulse and minute ventilation/carbon dioxide production slope. Peak systolic blood pressure increased from 120¡17 to 139¡21 mmHg. Combination treatment was well tolerated by all patients.It is concluded that the addition of the endothelin-receptor antagonist bosentan to inhaled iloprost or oral beraprost therapy appears to be safe for patients with primary pulmonary hypertension, resulting in a marked increase in exercise capacity. Therefore, rigorous studies should address whether combination treatment is more effective than either therapeutic intervention alone.

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“…Glyburide and cyclosporine A are contraindicated with concurrent bosentan therapy. Although a small study has shown that humans given bosentan 500 mg twice daily have reduced warfarin effect (35), no influence on warfarin activity has been seen in the clinical trials using the 125-mg and 250-mg twice-daily doses of bosentan.…”

Section: Safetymentioning

confidence: 99%

Endothelin receptor antagonists in pulmonary arterial hypertension

Channick

Sitbon

Barst

et al. 2004

Journal of the American College of Cardiology

159

104

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Endothelin receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension (PAH). Laboratory and clinical investigations have clearly shown that endothelin (ET)-1 is overexpressed in several forms of pulmonary vascular disease and likely plays a significant pathogenetic role in the development and progression of pulmonary vasculopathy. Oral endothelin receptor antagonists (ERAs) have been shown to improve pulmonary hemodynamics, exercise capacity, functional status, and clinical outcome in several randomized placebo-controlled trials. Bosentan, a dual-receptor antagonist, is approved by the U.S. Food and Drug Administration for class III and IV patients with PAH, based on two phase III trials. In addition to its efficacy as sole therapy, bosentan may have a role as part of a combination of drugs such as a prostanoid or sildenafil. The selective endothelin receptor-A antagonists sitaxsentan and ambrisentan are currently undergoing investigation.

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Effect of the Endothelin‐Receptor Antagonist Bosentan on the Pharmacokinetics and Pharmacodynamics of Warfarin

Cited by 76 publications

References 17 publications

The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers

The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers

Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids

Endothelin receptor antagonists in pulmonary arterial hypertension

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