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Regul Toxicol Pharmacol ; 64(1): 95-103, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22683289

ABSTRACT

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 It was withdrawn from the market due to an idiosyncratic risk of drug-induced liver injury identified from emerging clinical trial data and clinical case reports.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.


Subject(s)
Antihypertensive Agents/toxicity , Carcinogens/toxicity , Endothelin Receptor Antagonists , Hypertension, Pulmonary/drug therapy , Isoxazoles/toxicity , Thiophenes/toxicity , Alkaline Phosphatase/blood , Animals , Antihypertensive Agents/classification , Antihypertensive Agents/pharmacokinetics , Blood Coagulation/drug effects , Carcinogenicity Tests , Carcinogens/classification , Carcinogens/pharmacokinetics , Chemical and Drug Induced Liver Injury, Chronic/etiology , Chemical and Drug Induced Liver Injury, Chronic/metabolism , Chemical and Drug Induced Liver Injury, Chronic/pathology , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Erythrocyte Indices/drug effects , Female , Hypertrophy/chemically induced , Hypertrophy/pathology , Isoxazoles/classification , Isoxazoles/pharmacokinetics , Liver/drug effects , Liver/pathology , Liver/physiopathology , Liver Function Tests , Male , Mice , Mice, Inbred Strains , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , Risk Assessment , Species Specificity , Thiophenes/classification , Thiophenes/pharmacokinetics
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