An overview of the preclinical toxicity and potential carcinogenicity of sitaxentan (Thelin®), a potent endothelin receptor antagonist developed for pulmonary arterial hypertension.
Sitaxentan (Thelin®), an endothelin receptor antagonist with a long duration of action and high specificity for the endothelin receptor A subtype, was used to treat pulmonary arterial hypertension. It was withdrawn from the market due to an idiosyncratic risk of drug-induced liver injury identified from emerging clinical trial data and clinical case reports. The preclinical safety profile of sitaxentan is presented, including single- and repeat-dose toxicity in mice, rats, and dogs and carcinogenicity in mice and rats. Sitaxentan-related adverse effects included coagulopathy in rats and dogs, increased serum alkaline phosphatase activity in mice and dogs, and hepatic hypertrophy in all species. Decreased albumin, erythrocyte count, hemoglobin concentration and hematocrit, and increased coagulation times and liver weight were also noted. These effects generally occurred at systemic exposures (AUC(0-24)) that were substantially greater than those seen in humans. Twice-daily (vs. once daily) dosing resulted in increased toxicity, which correlated with increased trough plasma sitaxentan concentrations. Sitaxentan appeared to have a low potential for testicular and hepatic toxicity and was not carcinogenic. These studies suggested that sitaxentan would have a reasonable margin of safety when used as directed in humans and supported a positive benefit:risk assessment at the time of marketing approval.
Drug Safety Research and Development, Pfizer Research and Development Ltd., Sandwich, UK.
Keith
K
Owen
David M
DM
Cross
Mazin
M
Derzi
Elizabeth
E
Horsley
Fiona L
FL
Stavros
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D000959:Antihypertensive Agents / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*; D001777:Blood Coagulation / Q000187:drug effects; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*; D056487:Chemical and Drug Induced Liver Injury, Chronic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D065128:Endothelin Receptor Antagonists; D004909:Erythrocyte Indices / Q000187:drug effects; D005260:Female; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D006984:Hypertrophy / Q000139:chemically induced / Q000473:pathology; D007555:Isoxazoles / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013045:Species Specificity; D013876:Thiophenes / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*
D000959:Antihypertensive Agents; D002273:Carcinogens; D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles; D013876:Thiophenes; D000469:Alkaline Phosphatase; C106276:sitaxsentan