Background and Purpose: Apatinib is a small-molecule tyrosine kinase inhibitor for the treatment of recurrent or progressive advanced-stage gastric adenocarcinoma or gastroesophageal junction cancer. The in vitro inhibition studies suggested that apatinib exerted potent inhibition on CYP3A4 and CYP2C9. To evaluate the potential of apatinib as a perpetrator in CYP450-based drug–drug interactions in vivo, nifedipine and warfarin were, respectively, selected in the present study as the probe substrates of CYP3A4 and CYP2C9 for clinical drug–drug interaction studies. Since hypertension and thrombus are common adverse effects of vascular targeting anticancer agents, nifedipine and warfarin are usually coadministered with apatinib in clinical practice.
Methods: A single-center, open-label, single-arm, and self-controlled trial was conducted in patients with advanced solid tumors. The patients received a single dose of 30 mg nifedipine on Day 1/14 and a single dose of 3 mg warfarin on Day 3/16. On Day 9– 21, the subjects received a daily dose of 750 mg apatinib, respectively. The pharmacokinetics of nifedipine and warfarin in the absence or presence of apatinib was, respectively, investigated.
Results: Compared with the single oral administration, coadministration with apatinib contributed to the significant increases of AUC_{0– 48h} and C_max of nifedipine by 83% (90% confidence interval [CI] 1.46– 2.31) and 64% (90% CI 1.34– 2.01), respectively. Similarly, coadministration with apatinib contributed to the significant increases of AUC_0-t and C_max of S-warfarin by 92% (90% CI 1.68– 2.18) and 24% (90% CI 1.10– 1.39), respectively.
Conclusion: Concomitant apatinib administration resulted in significant increases in systemic exposure to nifedipine and S-warfarin. Owing to the risk of pharmacokinetic drug–drug interactions based on CYP3A4/CYP2C9 inhibition by apatinib, caution is advised in the concurrent use of apatinib with either CYP2C9 or CYP3A4 substrates.

Keywords: apatinib, drug-drug interaction, CYP3A4, CYP2C9, nifedipine, warfarin


中文翻译：

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阿帕替尼对晚期实体瘤患者硝苯地平和华法林药代动力学的影响。

背景与目的：阿帕替尼是一种小分子酪氨酸激酶抑制剂，用于治疗复发性或进展性晚期胃腺癌或胃食管结合部癌。体外抑制研究表明，阿帕替尼对 CYP3A4 和 CYP2C9 具有强效抑制作用。为了评估阿帕替尼在基于 CYP450 的体内药物-药物相互作用中作为肇事者的潜力，本研究中分别选择硝苯地平和华法林作为 CYP3A4 和 CYP2C9 的探针底物用于临床药物-药物相互作用研究。由于高血压和血栓是血管靶向抗癌药物的常见不良反应，临床实践中硝苯地平和华法林通常与阿帕替尼联合给药。
方法：在晚期实体瘤患者中进行了一项单中心、开放标签、单臂和自我对照试验。患者在第 1/14 天接受单剂量 30 mg 硝苯地平，在第 3/16 天接受单剂量 3 mg 华法林。在第 9-21 天，受试者分别接受了 750 mg 阿帕替尼的每日剂量。分别研究了阿帕替尼不存在或存在时硝苯地平和华法林的药代动力学。
结果：与单次口服给药相比，与阿帕替尼联合给药有助于显着增加 AUC _0-48h和_Cmax硝苯地平分别降低了 83%（90% 置信区间 [CI] 1.46–2.31）和 64%（90% CI 1.34–2.01）。_{同样，与阿帕替尼合用导致 S-华法林的 AUC 0-t}和 C _max分别显着增加92% (90% CI 1.68–2.18) 和 24% (90% CI 1.10–1.39)。
结论：伴随阿帕替尼给药导致全身暴露于硝苯地平和 S-华法林的显着增加。由于基于阿帕替尼抑制 CYP3A4/CYP2C9 的药代动力学药物相互作用的风险，建议在阿帕替尼与 CYP2C9 或 CYP3A4 底物同时使用时谨慎。

关键词：阿帕替尼，药物相互作用，CYP3A4，CYP2C9，硝苯地平，华法林