Bosentan modestly enhanced metabolism of warfarin and reduced its anticoagulant effects in one study and in one case a patient needed a 64 % increase in her warfarin dose after takingbosentan
In a double-blind,randomised, placebo-controlled, crossover study, 12 healthy subjects were given bosentan 500mg twice daily or placebo for 10 days, with a single 26mg dose of warfarin on day 6. Bosentan reduced AUC of R-warfarin by 38 % and of S-warfarin by 29%. A significant decrease in anticoagulant effects of warfarin was also noted, with a 23 % reduction in prothrombin time occurring with bosentan (See reference number 1).
One case highlights clinical significance of this interaction. A 35year-old woman taking warfarin with a stable INR of 2 to 3 over three months started taking bosentan 62.5mg twice daily. After 10 days her INR was 1.7, and remained at this level over next 4 weeks, despite an increase in her weekly warfarin dose from 27.5 to 40 mg. The bosentan dose was then increased to maintenance dose of 125mg twice daily, and two further weekly increases in warfarin dose were made. The INR was then high (3.2 to 4.1) for 3 weeks,before she was finally stabilised on warfarin 45mg each week (See reference number 2).
However, manufacturer of bosentan notes that, in clinical experience, use of bosentan with warfarin did not result in clinically relevant changes in INR or warfarin dose. There was no difference in frequency of warfarin dose changes (due to INR changes or adverse effects) between bosentan or placebo recipients (See reference number 3).
It has been suggested that bosentan induces both cytochrome P450 isoenzymes CYP3A4 and CYP2C9, which are involved in metabolism of R-warfarin and S-warfarin, respectively (See reference number 1).
Both reports suggest that a clinically significant interaction between warfarin and bosentan is possible, although exactly how frequently this may occur is unclear, since it was not detected in clinical studies. However, INR should be closely monitored in any patient taking warfarin during period that bosentan is started or stopped, or if dose is altered (See reference number 3).
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