PURPOSE: Ambrisentan is a high affinity, propanoic acid-class, ETA-selective endothelin receptor antagonist (ERA) with once-daily oral doses that are 10-100 times lower than sulfonamide-class ERAs for pulmonary arterial hypertension (PAH). Ambrisentan doses of 2.5 and 5 mg once-daily have been shown to improve 6-minute walk distance (6MWD) and delay clinical worsening in a placebo-controlled study of patients with PAH (ARIES-2), with no incidence of serum aminotransferases >3xULN (LFT abnormalities). To further evaluate the safety of ambrisentan, an open-label study was conducted of patients who had previously discontinued bosentan, sitaxsentan, or both therapies due to LFT abnormalities.
METHODS: Patients received 2.5 mg qd ambrisentan for 4 weeks, 5 mg qd ambrisentan for 20 weeks, and 2.5, 5, or 10 mg qd ambrisentan, thereafter. The primary endpoint was the incidence of LFT abnormalities during 12 weeks of therapy that were related to ambrisentan and resulted in discontinuation of drug.
RESULTS: A total of 36 patients who had previously discontinued bosentan (86%), sitaxsentan (6%), or both therapies (8%) due to LFT abnormalities were enrolled. The median duration of ERA therapy prior to discontinuation was 9 weeks. 64% of patients had idiopathic PAH and 36% had PAH associated with other etiologies. After 12 weeks of therapy, no patients had a recurrence of LFT abnormalities that required discontinuation of ambrisentan. One patient had an isolated incidence of LFT abnormalities that resulted in a temporary dose reduction. Patients continued to receive ambrisentan (mean exposure = 32 weeks, maximum exposure = 48 weeks) and no further LFT abnormalities were observed. Adverse events appeared similar to results from previous ambrisentan clinical studies.
CONCLUSION: No significant LFT abnormalities were observed with long-term ambrisentan administration in patients who had previously discontinued bosentan, sitaxsentan, or both therapies due to LFT abnormalities.
CLINICAL IMPLICATIONS: Ambrisentan appears to be a treatment option for patients who have previously discontinued ERA therapy due to LFT abnormalities and may provide an improved risk-to-benefit ratio for ERA therapy in patients with PAH.
DISCLOSURE: Michael McGoon, Consultant fee, speaker bureau, advisory committee, etc. Myogen Inc.; Product/procedure/technique that is considered research and is NOT yet approved for any purpose, ambrisentan.