An overview of the preclinical toxicity and potential carcinogenicity of sitaxentan (Thelin®), a potent endothelin receptor antagonist developed for pulmonary arterial hypertension

Article ID	Journal	Published Year	Pages	File Type
5857141	Regulatory Toxicology and Pharmacology	2012	9 Pages	PDF

Abstract

âº Sitaxentan preclinical safety was assessed in mice, rats, and dogs. âº Coagulopathy, increased serum alkaline phosphatase, hepatic hypertrophy and decreased blood parameters were observed. âº Effects occurred at exposures substantially greater than human therapeutic exposure. âº Sitaxentan showed a low potential for testicular and hepatic toxicity and was not carcinogenic. âº The pattern of sitaxentan toxicity could be characterized as an exaggeration of its pharmacological mechanism of action.

Keywords

NOAEL ETA CMC BSEP PAH MTD GLP APTT mmHg ALT RBC ETRA HCT AUC AST Aspartate aminotransferase Drug-induced liver injury ALP Alkaline phosphatase endothelin receptor antagonist Risk assessment Drug evaluation endothelin endothelin A receptor Testis red blood cell count Good Laboratory Practice Maximum tolerated dose twice daily DILI activated partial thromboplastin time prothrombin time Toxicity Toxicology Hemoglobin concentration Pulmonary arterial hypertension area under the curve millimeters of mercury hematocrit No observed adverse effect level Bile salt export pump Preclinical BID carboxymethylcellulose Endothelin receptor once daily