Bristol Myers Squibb, 556 Morris Ave, Summit, NJ, 07901, USA.
Altasciences/Vince and Associates, Overland Park, KS, USA.
Cancer Chemother Pharmacol. 2020 May;85(5):995-1001. doi: 10.1007/s00280-020-04074-4. Epub 2020 Apr 22.
Fedratinib, an oral, selective Janus kinase 2 inhibitor with activity against both wild-type and mutant Janus kinase 2, has pH-dependent solubility, with free solubility at pH 1. Concomitant administration of drugs that reduce gastric acid secretion, such as pantoprazole, may decrease the absorption of fedratinib and affect patient outcomes. The aim of this study was to evaluate the impact of 7-day repeated 40-mg doses of pantoprazole on the pharmacokinetic (PK) properties of a single 500-mg dose of fedratinib in healthy male subjects.
In this phase I, single-center, open-label, two-period, two-treatment, fixed-sequence crossover study, healthy male subjects were administered a single dose of fedratinib 500 mg on day 1 in Period 1, followed by pantoprazole 40 mg daily for 7 days (day 1 to day 7) and a single dose of fedratinib 500 mg on day 7 in Period 2. After the discontinuation of nine subjects due to vomiting, the protocol was amended to provide ondansetron as antiemetic prophylaxis to an additional ten enrolled subjects.
Twenty-six subjects were included. Repeated doses of pantoprazole 40 mg resulted in clinically insignificant increases in fedratinib exposure. Maximum plasma concentration increased by 1.09-fold and area under the plasma concentration-time curve from time 0 to infinity increased by 1.15-fold. All treatment-emergent adverse events were mild or moderate, except for one instance of neutropenia, which was considered unrelated to study intervention.
Coadministration with pantoprazole did not have clinically meaningful effects on fedratinib PK. No new or unexpected safety signals were observed with fedratinib.
Fedratinib 是一种口服、选择性 Janus 激酶 2 抑制剂，对野生型和突变型 Janus 激酶 2 均有活性，其溶解度随 pH 值变化，在 pH 值为 1 时具有游离溶解度。同时使用降低胃酸分泌的药物，如泮托拉唑，可能会降低 fedratinib 的吸收并影响患者的结局。本研究旨在评估 7 天重复给予 40mg 泮托拉唑对健康男性单次给予 500mg fedratinib 时的药代动力学（PK）特性的影响。
这是一项在健康男性中进行的、单中心、开放性、两周期、两治疗、固定序列交叉研究。在第 1 周期中，受试者于第 1 天单次给予 fedratinib 500mg，在第 1 天至第 7 天每天给予泮托拉唑 40mg，在第 2 周期中于第 7 天单次给予 fedratinib 500mg。由于呕吐，有 9 名受试者停止试验，因此修订了方案，对另外 10 名入组的受试者提供昂丹司琼作为止吐预防。
共有 26 名受试者入组。重复给予泮托拉唑 40mg 可使 fedratinib 的暴露量增加，但无临床意义。最大血药浓度增加 1.09 倍，从 0 时到无穷大的血药浓度-时间曲线下面积增加 1.15 倍。所有治疗期间出现的不良事件均为轻度或中度，除 1 例中性粒细胞减少外，均认为与研究干预无关。
与泮托拉唑同时使用对 fedratinib 的 PK 无临床意义的影响。fedratinib 未观察到新的或意外的安全性信号。
