Pfizer Inc, Groton, CT, USA.
Pfizer Clinical Research Unit, Brussels, Belgium.
Clin Pharmacol Drug Dev. 2014 Jan;3(1):72-7. doi: 10.1002/cpdd.71. Epub 2013 Oct 8.
Tofacitinib is a novel, oral JAK inhibitor that is being investigated as a targeted immunomodulator. Tofacitinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Two Phase 1, randomized, open-label, single sequence studies in 24 healthy subjects (12 per study) characterized the effects of fluconazole (moderate CYP3A4/potent CYP2C19 inhibitor) and ketoconazole (potent CYP3A4 inhibitor) on tofacitinib pharmacokinetics. In the fluconazole study, subjects received a single tofacitinib 30 mg dose. After 72 hours, subjects received fluconazole 400 mg, followed by 200 mg once daily (QD; days 2-7) plus tofacitinib 30 mg on day 5. In the ketoconazole study, a single tofacitinib 10 mg dose was administered. After 24 hours, subjects received ketoconazole (400 mg QD; days 1-3) plus tofacitinib 10 mg on day 3. Treatment comparisons were made using mixed-effect models. Tofacitinib area under the curve and maximal plasma concentration increased by 79% and 27%, respectively, with fluconazole co-administration and by 103% and 16%, respectively, with ketoconazole co-administration. Tofacitinib half-life increased by approximately 1 hour during co-administration with fluconazole or ketoconazole. Co-administration of moderate to potent CYP3A4 inhibitors is likely to increase the systemic exposure of tofacitinib and thus may warrant dosage adjustments or restrictions.
托法替布是一种新型的口服 JAK 抑制剂，作为一种靶向免疫调节剂正在研究中。托法替布主要通过细胞色素 P450（CYP）3A4 代谢，其次是 CYP2C19。两项在 24 例健康受试者（每项研究 12 例）中进行的 1 期、随机、开放标签、单序列研究，描述了氟康唑（中度 CYP3A4/强 CYP2C19 抑制剂）和酮康唑（强 CYP3A4 抑制剂）对托法替布药代动力学的影响。在氟康唑研究中，受试者接受单次托法替布 30mg 剂量。72 小时后，受试者给予氟康唑 400mg，随后每天 200mg 一次（QD；第 2-7 天），第 5 天加用托法替布 30mg。在酮康唑研究中，给予单次托法替布 10mg 剂量。24 小时后，受试者给予酮康唑（QD 400mg；第 1-3 天），第 3 天给予托法替布 10mg。采用混合效应模型进行治疗比较。与氟康唑合用使托法替布的 AUC 和 Cmax 分别增加 79%和 27%，与酮康唑合用使 AUC 和 Cmax 分别增加 103%和 16%。与氟康唑或酮康唑合用时，托法替布的半衰期增加约 1 小时。中度至强 CYP3A4 抑制剂的合用可能会增加托法替布的全身暴露，因此可能需要调整剂量或限制使用。
