Bristol Myers Squibb, 556 Morris Ave, Summit, NJ, 07901, USA.
Alliance for Multispecialty Research, University of Tennessee, Knoxville, TN, USA.
Cancer Chemother Pharmacol. 2020 Jun;85(6):1109-1117. doi: 10.1007/s00280-020-04084-2. Epub 2020 May 24.
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.
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.
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 (AUC) 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 AUC did not appreciably differ between subjects with mild HI and matched healthy subjects. Overall, most treatment-emergent adverse events were gastrointestinal and mild.
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.
Fedratinib 是一种口服、选择性 Janus 激酶 2 抑制剂，已获美国批准用于治疗中危-2 级或高危骨髓纤维化患者。本研究旨在评估 Fedratinib 在肾功能不全（RI）和肝功能不全（HI）受试者中的药代动力学和耐受性。
在 RI 研究中，纳入了慢性稳定的轻、中、重度 RI 以及终末期肾病的男性和女性受试者。HI 研究纳入了慢性稳定的轻度 HI 受试者。这两项研究均为多中心、开放标签、单次给药的 1 期研究，包括匹配的健康受试者。受试者第 1 天单次口服 Fedratinib 300mg，第 4 天出院，第 5-12 天进行临床访视，并于第 14-16 天进行研究结束访视。
RI 研究和 HI 研究分别纳入 36 例和 17 例受试者。在 RI 研究中，与匹配的健康受试者相比，重度和中度 RI 受试者的 Fedratinib 血药浓度-时间曲线下面积（AUC）分别增加了 1.9 倍和 1.5 倍。在 HI 研究中，轻度 HI 受试者与匹配的健康受试者的 Fedratinib AUC 无显著差异。总体而言，大多数治疗相关不良事件为胃肠道不良事件，程度较轻。
轻度 RI 和 HI 不需要调整 Fedratinib 剂量。中度 RI 患者应进行监测（必要时调整剂量），而重度 RI 患者应接受每日 200mg 的剂量，低于推荐的 400mg 剂量。
