PURPOSE Fedratinib is an oral, selective Janus kinase 2 inhibitor that is approved in the United States for the treatment of patients with intermediate-2 or high-risk myelofibrosis. Pharmacokinetics and tolerability of fedratinib in subjects with renal impairment (RI) and hepatic impairment (HI) were evaluated in two separate studies. METHODS In the renal study, male and female subjects with stable, chronic mild, moderate, and severe RI, as well as those with end-stage renal disease, were included. The hepatic study included subjects with stable, chronic mild HI. Both were phase 1, multicenter, open-label, single-dose studies, and included matched healthy subjects. Subjects received a single oral dose of fedratinib 300 mg on day 1, were discharged on day 4, returned for clinical visits on days 5-12, and had their end-of-study visit between days 14 and 16. RESULTS Thirty-six and 17 subjects were included in the renal and hepatic studies, respectively. In the renal study, fedratinib area under the plasma concentration-time curve from time 0 to infinity (AUCinf) was 1.9- and 1.5-fold higher in subjects with severe and moderate RI, respectively, than in matched healthy subjects. In the hepatic study, fedratinib AUCinf did not appreciably differ between subjects with mild HI and matched healthy subjects. Overall, most treatment-emergent adverse events were gastrointestinal and mild. CONCLUSION Mild RI and HI do not necessitate fedratinib dosage adjustments. Subjects with moderate RI should be monitored (with dosage adjustments made as necessary), whereas those with severe RI should receive a daily dose of 200 mg, reduced from the indicated dose of 400 mg.

中文翻译：

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fedratinib 是一种口服的选择性 Janus 激酶 2 抑制剂，在肾或肝功能不全的受试者中的药代动力学和耐受性。

目的 Fedratinib 是一种口服的选择性 Janus 激酶 2 抑制剂，在美国被批准用于治疗中度 2 或高危骨髓纤维化患者。在两项独立的研究中评估了 Fedratinib 在肾受损 (RI) 和肝受损 (HI) 受试者中的药代动力学和耐受性。方法 在肾脏研究中，包括患有稳定、慢性轻度、中度和重度 RI 的男性和女性受试者，以及患有终末期肾病的受试者。肝脏研究包括患有稳定、慢性轻度 HI 的受试者。两者都是 1 期、多中心、开放标签、单剂量研究，并包括匹配的健康受试者。受试者在第 1 天接受单次口服剂量的 fedratinib 300 mg，第 4 天出院，第 5-12 天返回临床就诊，并在第 14 天和第 16 天之间进行了研究结束访问。结果 肾和肝研究分别包括 36 名和 17 名受试者。在肾脏研究中，重度和中度 RI 受试者从时间 0 到无穷大的血浆浓度-时间曲线下的 Fedratinib 面积（AUCinf）分别比匹配的健康受试者高 1.9 倍和 1.5 倍。在肝脏研究中，fedratinib AUCinf 在轻度 HI 受试者和匹配的健康受试者之间没有明显差异。总体而言，大多数治疗出现的不良事件是胃肠道和轻微的。结论 轻度 RI 和 HI 不需要调整 Fedratinib 的剂量。应监测中度 RI 的受试者（必要时调整剂量），而重度 RI 的受试者应接受 200 mg 的每日剂量，