Bristol Myers Squibb, 556 Morris Ave, Summit, NJ, 07901, USA.
Sanofi, Bridgewater, NJ, USA.
Cancer Chemother Pharmacol. 2020 May;85(5):899-906. doi: 10.1007/s00280-020-04067-3. Epub 2020 Apr 4.
Fedratinib is an orally administered Janus kinase 2-selective inhibitor that is indicated for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis in the United States. Fedratinib is metabolized by multiple cytochrome P450s (CYPs) in vitro, with the predominant contribution from CYP3A4. The primary objective of this study was to evaluate the effects of 14-day repeated 200 mg twice daily (BID) oral doses of a strong CYP3A4 inhibitor, ketoconazole, on a sequential ascending single oral dose of fedratinib in healthy male subjects.
An open-label, fixed-sequence, two-treatment cross-over study was conducted. Two cohorts of healthy adult males received two single doses of fedratinib (50 mg in Cohort 1 and 300 mg in Cohort 2) with one dose administered alone on Day 1 of Period 1 and the other dose coadministered with ketoconazole in the morning of Day 6 of Period 2. Subjects in both cohorts received 200-mg BID (Days 1-14) ketoconazole during Period 2.
Coadministration of repeated 200-mg BID oral doses of ketoconazole for 14 days increased fedratinib exposure by 3.85- and 3.06-fold for area under the plasma concentration-time curve from time zero to infinity following a single oral dose of fedratinib of 50 and 300 mg, respectively. Oral administration of a single dose of 50 or 300 mg of fedratinib, administered alone or coadministered with steady-state ketoconazole, was safe and tolerable in the healthy male subjects.
These results serve as the basis for fedratinib dose reduction when fedratinib is coadministered with strong CYP3A4 inhibitors.
Fedratinib 是一种口服 Janus 激酶 2 选择性抑制剂，适用于美国患有中间 2 或高危骨髓纤维化的成年患者。Fedratinib 在体外通过多种细胞色素 P450（CYP）代谢，主要由 CYP3A4 贡献。本研究的主要目的是评估 14 天重复 200mg 每日两次（BID）口服剂量的强 CYP3A4 抑制剂酮康唑对健康男性单次口服递增 fedratinib 的影响。
进行了一项开放标签、固定序列、两治疗交叉研究。两队列健康成年男性接受了 fedratinib 的两次单剂量（队列 1 为 50mg，队列 2 为 300mg），其中一剂于第 1 天的第 1 期第 1 天单独给药，另一剂与第 2 期第 6 天的酮康唑在早上给药。两个队列的受试者在第 2 期均接受了 200mg BID（第 1-14 天）酮康唑。
酮康唑重复 200mg BID 口服剂量 14 天共给药增加了 fedratinib 的暴露量，在单剂量 fedratinib 50mg 和 300mg 时，fedratinib 血浆浓度-时间曲线从零到无穷大的下的 AUC 分别增加了 3.85 倍和 3.06 倍。单独或与稳态酮康唑联合给药时，健康男性受试者单次口服 50mg 或 300mg fedratinib 是安全和耐受的。
这些结果为 fedratinib 与强 CYP3A4 抑制剂联合使用时的剂量减少提供了依据。
