Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
J Clin Pharmacol. 2018 Mar;58(3):347-356. doi: 10.1002/jcph.1016. Epub 2017 Oct 2.
Apatinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with advanced-stage gastric cancer or gastroesophageal junction cancer who have progressed or recurred after at least 2 kinds of systemic chemotherapy. In vitro data indicate that cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of apatinib. Pharmacokinetic drug-drug interactions of apatinib and (1) a CYP3A4 inducer (rifampin) or (2) a CYP3A inhibitor (itraconazole) were clinically evaluated in healthy volunteers. Compared with the single administration of apatinib, its coadministration with rifampin resulted in a 5.6-fold plasma clearance (CL/F) and 83% decrease in plasma AUC of apatinib. By contrast, coadministration with itraconazole reduced the CL/F of apatinib by 40% and increased its AUC by 75%. In summary, a strong CYP3A4 inducer (rifampin) had a strong effect (>5-fold) on the clinical pharmacokinetics of apatinib, whereas a strong CYP3A inhibitor (itraconazole 100 mg once a day) had a weak effect (1.25- to 2-fold). Whether these effects are of clinical significance needs further research and information about the exposure-safety and exposure-efficacy relationship of apatinib.
阿帕替尼是一种小分子酪氨酸激酶抑制剂，已被批准用于治疗至少接受过 2 种全身化疗后进展或复发的晚期胃或胃食管交界处腺癌患者。体外数据表明细胞色素 P450（CYP）3A4 是参与阿帕替尼代谢的主要 CYP 同工酶。在健康志愿者中临床评估了阿帕替尼与（1）CYP3A4 诱导剂（利福平）或（2）CYP3A 抑制剂（伊曲康唑）的药代动力学药物相互作用。与单药阿帕替尼相比，与利福平合用使阿帕替尼的血浆清除率（CL/F）增加 5.6 倍，血浆 AUC 减少 83%。相比之下，与伊曲康唑合用使阿帕替尼的 CL/F 降低 40%，AUC 增加 75%。总之，强 CYP3A4 诱导剂（利福平）对阿帕替尼的临床药代动力学有很强的影响（>5 倍），而强 CYP3A 抑制剂（伊曲康唑 100mg 每日 1 次）的影响较弱（1.25-2 倍）。这些影响是否具有临床意义需要进一步研究和了解阿帕替尼的暴露-安全性和暴露-疗效关系。
