Drug Safety Research and Development, Pfizer Research and Development Ltd., Sandwich, UK.
Regul Toxicol Pharmacol. 2012 Oct;64(1):43-50. doi: 10.1016/j.yrtph.2012.05.018. Epub 2012 Jun 5.
Pulmonary arterial hypertension (PAH) is characterized by increasing pulmonary vascular resistance leading to right heart failure and death. Sitaxentan (Thelin®) demonstrated efficacy in adult PAH; however, PAH therapy for children is critically needed. To support development for pediatric patients, sitaxentan (10, 30, or 60mg/kg/day) toxicity was assessed in juvenile (postnatal day 22-14weeks) 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 60mg/kg/day; for toxicity, the NOAEL was 30mg/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 (100mg/day). This study is discussed in the context of evolving European pediatric drug legislation and guidance.
肺动脉高压（PAH）的特征是肺血管阻力不断增加，导致右心衰竭和死亡。西他生坦（Thelin®）已被证明可有效治疗成人 PAH；然而，儿童 PAH 的治疗方法仍亟待研究。为了支持儿科患者的开发，在幼年（出生后第 22-14 周）大鼠中评估了西他生坦（10、30 或 60mg/kg/天）的毒性。西他生坦未影响生存、临床症状或体重；未确定毒性靶器官。血液学变化包括红细胞参数降低、凝血酶原时间和部分凝血活酶时间延长。通过交配性能评估，雄性和雌性的生殖发育和功能均未受影响；生育力、发情周期和正常妊娠维持至中期妊娠；精子计数、形态和活力；以及睾丸变化。生殖发育和功能的无明显不良效应水平（NOAEL）为 60mg/kg/天；毒性的 NOAEL 为 30mg/kg/天（凝血参数变化）。西他生坦在暴露量分别为治疗暴露（100mg/天）后成人的 58 倍和 61 倍时，未对身体发育、认知能力或生殖功能产生不良影响。本文将结合不断发展的欧洲儿科药物立法和指导意见进行讨论。
