Evaluation of sitaxentan (Thelin®) toxicity in juvenile rats and regulatory interactions during the development of a European Medicines Agency pediatric investigation plan

Pulmonary arterial hypertension (PAH) is characterized by increasing pulmonary vascular resistance leading to right heart failure and death. Sitaxentan (Thelin (R)) demonstrated efficacy in adult PAH; however, PAH therapy for children is critically needed. To support development for pediatric patients, sitaxentan (10, 30, or 60 mg/kg/day) toxicity was assessed in juvenile (postnatal day 22-14 weeks) rats. Sitaxentan did not affect survival, clinical signs, or body weight; no target organ of toxicity was identified. Hematologic changes were decreased erythrocyte parameters, prothrombin time, and activated partial thromboplastin time. Reproductive development and function in both sexes was unaffected, as assessed by mating performance; fertility, estrous cyclicity, and maintenance of normal pregnancy up to mid-gestation; sperm count, morphology, and motility; and testicular changes. The no-observed-adverse-effect level (NOAEL) on reproductive development and function was 60 mg/kg/day; for toxicity, the NOAEL was 30 mg/kg/day (coagulation parameter changes). Sitaxentan did not adversely affect physical development, cognitive ability, or reproductive function at exposures that were 58- and 61-fold higher than those found in adults after therapeutic exposure (100 mg/day). This study is discussed in the context of evolving European pediatric drug legislation and guidance. (C) 2012 Elsevier Inc. All rights reserved.