PURPOSE: Ambrisentan is a high affinity, propanoic acid-class, ETA-selective endothelin receptor antagonist (ERA). Ambrisentan doses of 2.5 and 5 mg once-daily have been shown to improve 6-minute walk distance and delay clinical worsening in a placebo-controlled study (ARIES-2) of patients with pulmonary arterial hypertension (PAH), with no incidence of serum aminotransferases >3xULN. Warfarin anticoagulation therapy is common for patients with PAH. When coadministered, sulfonamide-class ERAs have been shown to induce (bosentan) or inhibit (sitaxsentan) the p450-dependent metabolism of warfarin and alter the pharmacokinetic (PK) and pharmacodynamic (PD) effects of warfarin. Therefore, the potential for ambrisentan to affect the PK or PD of warfarin was examined.
METHODS: 22 healthy adults received a 25 mg dose of racemic warfarin alone and after 8 days of ambrisentan 10 mg qd. R- and S-warfarin plasma concentrations were measured over a 96-hour period and exposure (AUC0-last) and maximum plasma concentration (Cmax) were determined. Prothrombin time was measured over a 96-hour period and cumulative prothrombin time (PTAUC) and maximum prothrombin time (PTmax) were assessed.
RESULTS: Slight increases in AUC0-last were observed for R- and S-warfarin after 8 days of ambrisentan administration (+4.7% [90% CI: +1.7% to +7.7%] and +1.9% [90% CI: −1.4% to +5.3%], respectively), whereas, Cmax for R- and S-warfarin were decreased (−8.4% [90% CI: −13.8% to −2.6%] and −10.1% [90% CI: −15.2% to −4.7%], respectively). The PTAUC and PTmax associated with warfarin administration were decreased slightly with concomitant ambrisentan administration (−6.6% [95% CI: −8.7% to −4.6%] and −14.2% [95% CI: −16.6 to −11.8], respectively). Confidence intervals for all PK and PD parameters were within the pre-specified equivalence criteria.
CONCLUSION: Ambrisentan administration had little effect on the AUC0-last or Cmax of R- or S-warfarin. A slight reduction in prothrombin time was observed for a single-dose of warfarin following ambrisentan administration. However, based on confidence intervals, all changes in warfarin PK and PD were not considered to be clinically relevant.
CLINICAL IMPLICATIONS: Dosage adjustment for warfarin therapy should not be required with concomitant ambrisentan administration.
DISCLOSURE: Michael Gerber, Employee Myogen, Inc.; Product/procedure/technique that is considered research and is NOT yet approved for any purpose, ambrisentan.