Pfizer Inc., Groton, CT 06340-8012, USA.
Br J Clin Pharmacol. 2012 Jul;74(1):109-15. doi: 10.1111/j.1365-2125.2012.04168.x.
• Tofacitinib (CP-690,550) is a novel, oral Janus kinase inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis. • Non-renal elimination accounts for 70% of the total clearance of tofacitinib and the metabolism is primarily mediated by cytochrome P450 (CYP) 3A4. • This study was required to determine the effect of tofacitinib on the in vivo pharmacokinetics of a sensitive CYP3A4 substrate.
• The pharmacokinetics of midazolam, a sensitive CYP3A4 substrate, are not altered when co-administered with tofacitinib in healthy subjects. • Tofacitinib is unlikely to affect the clearance of drugs metabolized by CYP enzymes. • There is no need for dose adjustments of CYP substrates when co-administered with tofacitinib.
To investigate inhibitive and inductive effects of tofacitinib (CP-690,550), a Janus kinase inhibitor, on CYP3A4 function via in vitro and in vivo studies.
In vitro experiments were conducted to assess the inhibition and induction potential of tofacitinib for major drug metabolizing enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). A phase 1, randomized, open-label, two-way crossover study (NCT00902460) was conducted to confirm the lack of inhibitive/inductive effect on a sensitive CYP3A4 substrate, midazolam, in healthy subjects. Midazolam pharmacokinetics were assessed over 24 h following single dose 2 mg administration prior to administering tofacitinib and after twice daily dosing of tofacitinib 30 mg for 6 days. The primary endpoint was midazolam area under the concentration-time profile, from time 0 to infinity (AUC(0,∞)).
In vitro studies demonstrated low potential for CYP inhibition (IC(50) estimates tofacitinib > 30 µm), CYP3A4 mRNA induction (observed at tofacitinib concentrations ≥ 25 µm) and no effect on enzymatic activity of CYP substrates. In the human study, AUC(0,∞) adjusted geometric mean ratio for midazolam plus tofacitinib to midazolam alone was 103.97% [90% confidence interval (CI) 95.57, 113.12], wholly within the pre-specified acceptance region (80, 125). The 90% CI for the ratio of adjusted geometric means of maximum plasma concentration (C(max) ) (95.98, 108.87) was also wholly within this acceptance region.
These data confirm a lack of an inhibitive or inductive effect of tofacitinib on CYP3A activity in humans and, in conjunction with in vitro data, support the conclusion that tofacitinib is unlikely to influence the CYP enzyme system as a whole.
托法替尼（CP-690,550）是一种新型口服 Janus 激酶抑制剂，作为类风湿关节炎的靶向免疫调节剂和疾病修饰疗法进行研究。
非肾脏清除占托法替尼总清除率的 70%，其代谢主要由细胞色素 P450（CYP）3A4 介导。
本研究旨在确定托法替尼对敏感 CYP3A4 底物体内药代动力学的影响。
健康受试者同时给予托法替尼时，咪达唑仑（一种敏感 CYP3A4 底物）的药代动力学不受影响。
托法替尼不太可能影响 CYP 酶代谢的药物的清除率。
当与托法替尼同时给药时，无需调整 CYP 底物的剂量。
通过体外和体内研究，研究 Janus 激酶抑制剂托法替尼（CP-690,550）对 CYP3A4 功能的抑制和诱导作用。
进行了体外实验，以评估托法替尼对主要药物代谢酶（CYP1A2、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6 和 CYP3A4）的抑制和诱导潜力。进行了一项 I 期、随机、开放标签、双向交叉研究（NCT00902460），以确认托法替尼对健康受试者敏感 CYP3A4 底物咪达唑仑无抑制/诱导作用。在给予托法替尼之前和托法替尼每日两次给药 30 mg 共 6 天后，给予单剂量 2 mg 咪达唑仑 24 小时后评估咪达唑仑的药代动力学。主要终点是咪达唑仑从时间 0 到无穷大（AUC（0，∞）的浓度-时间曲线下面积。
体外研究表明，CYP 抑制的潜力较低（IC50 估计托法替尼>30 µm），CYP3A4 mRNA 诱导（在托法替尼浓度≥25 µm 时观察到），对 CYP 底物的酶活性无影响。在人体研究中，咪达唑仑加托法替尼与咪达唑仑单独使用的 AUC（0，∞）调整后的几何均数比值为 103.97%[90%置信区间（CI）95.57，113.12]，完全在预设的接受区域（80，125）内。最大血浆浓度（C（max））调整后的几何均数比值的 90%CI（95.98，108.87）也完全在该接受区域内。
这些数据证实托法替尼对 CYP3A 活性无抑制或诱导作用，结合体外数据，支持托法替尼不太可能影响整个 CYP 酶系统的结论。
