Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities.
BACKGROUND
Some endothelin receptor antagonists (ERAs) are associated with liver function test (LFT) result abnormalities. However, ambrisentan has an incidence of serum aminotransferase levels more than three times the upper limit of normal (ULN), similar to that observed in PAH patients who are not receiving ERAs. Because ambrisentan may provide benefits in PAH patients who have discontinued ERA therapy due to LFT abnormalities, we evaluated the safety and efficacy of ambrisentan in this patient population.


METHODS
Patients who previously discontinued bosentan and/or sitaxsentan due to LFT abnormalities received ambrisentan, 2.5 mg qd, for 4 weeks followed by 5 mg/d for 8 weeks. The primary end point was the incidence of aminotransferase levels more than three times ULN considered by the investigator to be related to ambrisentan and resulting in drug discontinuation. Secondary end points included aminotransferase levels more than five times ULN requiring drug discontinuation and more than three times ULN requiring dose reduction, as well as changes in 6-min walk distance (6MWD), Borg dyspnea index, World Health Organization functional class, and Short Form-36 health survey score. Patients continued treatment beyond the 12-week end point with monthly monitoring of LFTs.


RESULTS
Thirty-six patients who previously discontinued bosentan (n = 31), sitaxsentan (n = 2), or both (n = 3) were enrolled. At baseline, 69.4% of patients were receiving prostanoid and/or sildenafil therapy. No patient had an aminotransferase level more than three times ULN that required ambrisentan discontinuation. One patient had a transient aminotransferase level more than three times ULN that resolved following a temporary dose reduction. No additional aminotransferase levels more than three times ULN were observed with long-term treatment (median exposure, 102 weeks), despite dose increases to 10 mg qd in more than half of the patients. Significant improvements in 6MWD and other efficacy assessments were observed.


CONCLUSIONS
Ambrisentan treatment may be an option for patients who have discontinued bosentan and/or sitaxsentan therapy due to LFT result abnormalities.


BACKGROUND
Clinicaltrials.gov Identifier NCT00423592.
McGoon
Michael D
MD
Mayo Clinic, Rochester, MN. Electronic address: mmcgoon@mayo.edu.
Frost
Adaani E
AE
Baylor College of Medicine, Houston, TX.
Oudiz
Ronald J
RJ
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrence, CA.
Badesch
David B
DB
University of Colorado, Denver, CO.
Galie
Nazzareno
N
University of Bologna, Bologna Italy.
Olschewski
Horst
H
Medical University-Graz, Austria.
McLaughlin
Vallerie V
VV
University of Michigan, MI.
Gerber
Michael J
MJ
Gilead Sciences, Westminster, CO.
Dufton
Chris
C
Gilead Sciences, Westminster, CO.
Despain
Darrin J
DJ
Gilead Sciences, Westminster, CO.
Rubin
Lewis J
LJ
University of California-San Diego, La Jolla, CA.
D000293:Adolescent; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000077300:Bosentan; D002648:Child; D018572:Disease-Free Survival; D065128:Endothelin Receptor Antagonists; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology*; D007555:Isoxazoles / Q000009:adverse effects / Q000627:therapeutic use; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D010666:Phenylpropionates / Q000627:therapeutic use*; D011724:Pyridazines / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use; D000637:Transaminases / Q000097:blood*; D016896:Treatment Outcome; D055815:Young Adult
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles; D010666:Phenylpropionates; D011724:Pyridazines; D013449:Sulfonamides; D013876:Thiophenes; D000637:Transaminases; C467894:ambrisentan; C106276:sitaxsentan; D000077300:Bosentan