Epidemiology

Ambrisentan not tied to liver damage

Last Updated: 2012-05-21 15:25:07 -0400 (Reuters Health)

By David Douglas

NEW YORK (Reuters Health) - A letter published May 12 in the Journal of the American College of Cardiology presents the data behind health regulators' decision to no longer require monthly liver function tests for patients receiving the endothelin A selective antagonist ambrisentan (Letairis, Gilead).

In response to these data, the U.S. Food and Drug Administration (FDA) dropped the requirement in 2011, although it maintained its requirement for a black box warning against use in pregnancy.

Dr. Ori Ben-Yehuda, who's employed by the Foster City, California, drugmaker Gilead, told Reuters Health by email that the findings "differentiate ambrisentan from other endothelin receptor antagonists and offer patients the convenience of an oral agent for pulmonary arterial hypertension without the inconvenience of mandatory monthly blood tests for liver function tests."

His company's post-marketing research showed that over 3.5 years, 10,927 U.S. patients received ambrisentan for pulmonary arterial hypertension, with a total exposure of 9,893 patient-years. Mean duration of use was 331 days, according to the authors of the report.

In all, there were 314 reports of hepatic events, including 79 confirmed as being clinically significant. Six of the 79 were possible "Hy's law" cases - that is, more than three times the upper limit of normal for alanine or aspartate amino transferase and more than twice the upper limit of normal for total bilirubin, indicating a high likelihood of drug hepatotoxicity -- but the researchers were able to come up with alternative explanations for the findings.

They were also able to identify possible alternative causes or contributing factors for 55 of the other 73 cases, and in 38 of these, ambrisentan was successfully restarted.

The researchers point out that pulmonary arterial hypertension "is itself associated with congestive liver disease due to transient or progressive right ventricular dysfunction." Moreover, in trials of endothelin receptor antagonists, elevated liver enzymes have been seen in up to 6% of placebo-treated patients with pulmonary arterial hypertension

The authors add that variations in the structure of different endothelin receptor antagonists may underlie differences in hepatic safety profiles. For example, hepatotoxicity black box warnings remain in place for bosentan (Tracleer, Actelion).

The team points out that "the black box warning against the use of ambrisentan in pregnancy was maintained, in keeping with the known teratogenicity of endothelin receptor antagonists."

SOURCE: http://bit.ly/KsLdVl

J Am Coll Cardiol 2012.