Shin Wonsuk, Yang A-Young, Yun Hyeonji, Cho Doo-Yeoun, Park Kyung Hee, Shin Hyunju, Kim Anhye
Department of Clinical Pharmacology and Therapeutics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Korea.
Clinical Development Center, Daewoong Pharmaceutical Co., Ltd., Seoul 06170, Korea.
Transl Clin Pharmacol. 2020 Sep;28(3):160-167. doi: 10.12793/tcp.2020.28.e13. Epub 2020 Sep 21.
Tofacitinib is an oral disease-modifying anti-rheumatic drug to selectively inhibit Janus kinases. Tofacitinib is a representative small molecule inhibitor that is used to treat many diseases including rheumatoid arthritis and various autoimmune conditions. Unlike biological agents, tofacitinib has several advantages, including the ability to be administered orally and a short half-life. This study aimed to evaluate the bioequivalence of the pharmacokinetics (PK) between tofacitinib aspartate 7.13 mg (test formulation) and tofacitinib citrate 8.08 mg (reference formulation; Xeljanz®) in healthy subjects. A randomized, open-label, single-dose, 2-sequence, 2-period, 2-treatment crossover trial was conducted in 41 healthy volunteers. A total of 5 mg of tofacitinib as the test or the reference formulation was administered, and serial blood samples were collected up to 14 hours after dosing for PK analyses. The plasma concentration of tofacitinib was determined by ultra-performance liquid chromatography-tandem mass spectrometry. A non-compartmental analysis was used to estimate the PK parameters. A total of 35 subjects completed the study and the study drug was well-tolerated. The mean maximum concentration (C) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC) for the test formulation were 52.67 ng/mL and 133.86 ng∙h/mL, respectively, and 50.61 ng/mL and 133.49 h∙ng/mL for the reference formulation, respectively. The geometric mean ratios (90% confidence intervals) of the C and AUC between the 2 formulations were 1.041 (0.944-1.148) and 1.003 (0.968-1.039), respectively. Tofacitinib aspartate exhibited bioequivalent PK profiles to those of the reference formulation.
ClinicalTrials.gov Identifier: NCT04278391.
托法替布是一种口服疾病修饰抗风湿药物，可选择性抑制 Janus 激酶。托法替布是一种代表性的小分子抑制剂，用于治疗多种疾病，包括类风湿性关节炎和各种自身免疫性疾病。与生物制剂不同，托法替布有几个优点，包括口服给药的能力和较短的半衰期。本研究旨在评估健康受试者中 7.13 mg 天门冬氨酸托法替布（试验制剂）和 8.08 mg 枸橼酸托法替布（参比制剂；Xeljanz®）的药代动力学（PK）生物等效性。在 41 名健康志愿者中进行了一项随机、开放标签、单剂量、2 序列、2 周期、2 治疗交叉试验。给予 5 mg 托法替布作为试验制剂或参比制剂，并在给药后长达 14 小时采集系列血样进行 PK 分析。通过超高效液相色谱-串联质谱法测定托法替布的血浆浓度。采用非房室分析来估计 PK 参数。共有 35 名受试者完成了研究，研究药物耐受性良好。试验制剂的平均最大浓度（C）和从零时间到最后可定量浓度时间的浓度-时间曲线下面积（AUC）分别为 52.67 ng/mL 和 133.86 ng∙h/mL，参比制剂分别为 50.61 ng/mL 和 133.49 h∙ng/mL。两种制剂之间 C 和 AUC 的几何平均比值（90%置信区间）分别为 1.041（0.944-1.148）和 1.003（0.968-1.039）。天门冬氨酸托法替布的 PK 特征与参比制剂具有生物等效性。
ClinicalTrials.gov 标识符：NCT04278391。
