In a letter published in the May 12th on-line Journal of the American College of Cardiology, Dr. Ori Ben-Yehuda and colleagues at the Foster City, California company, give details of the after-market research which led to the removal of the US Food and Drug Administration (FDA) label entry warning related to liver injury (See Reuters Health report 2011-03-04).
As Dr. Ben-Yehuda told Reuters Health by email, 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.”
Over 3.5 years, the researchers point out that 10,927 patients in the US received ambrisentan with a total exposure of 9893 patient-years. Mean ambrisentan use was for 330.5 days.
In all, there were 314 reports of hepatic events. Of these, 79 were confirmed as being clinically significant. Six were ruled out for a number of reasons. Possible alternative causes were also present in 55 of the remaining 73 patients and in 38 of these, ambrisentan was successfully restarted.
The researchers also observe that “PAH is itself associated with congestive liver disease due to transient or progressive right ventricular dysfunction.” Moreover, in trials of endothelin receptor antagonists, an incidence of elevated aminotransferase levels of up to 6% has been reported in placebo-treated patients with PAH.
They add that differences 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 concludes that the liver related warning for ambrisentan was removed in March of 2011 but “the black box warning against the use of ambrisentan in pregnancy was maintained, in keeping with the known teratogenicity of endothelin receptor antagonists.”