Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2022-08-06 , DOI: 10.1007/s40262-022-01144-z Ariel Topletz-Erickson 1 , Anthony Lee 2 , Evelyn L Rustia 3, 4 , Hao Sun 2 , JoAl G Mayor 3 , Layth I Abdulrasool 3 , Luke Walker 3 , Christopher J Endres 1
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Background and Objective
Tucatinib is approved for treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Understanding potential drug–drug interactions (DDIs) informs proper dosing when co-administering tucatinib with other therapies. The aim of this study was to evaluate DDIs between tucatinib and metabolizing enzymes and transporters in healthy volunteers.
Methods
Parts A–C assessed the impact of itraconazole (cytochrome P450 [CYP] 3A4 inhibitor), rifampin (CYP3A4/CYP2C8 inducer), or gemfibrozil (CYP2C8 inhibitor) on the pharmacokinetics of a single 300 mg dose of tucatinib administered orally and its primary metabolite, ONT-993. Parts D and E assessed the effect of steady-state tucatinib on the pharmacokinetics of repaglinide (CYP2C8 substrate), tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), and digoxin (P-glycoprotein substrate).
Results
Tucatinib area under the concentration–time curve from time 0 extrapolated to infinity (AUC0–inf) increased by ~ 1.3- and 3.0-fold with itraconazole and gemfibrozil, respectively, and decreased by 48% with rifampin, indicating that tucatinib is metabolized primarily by CYP2C8, and to a lesser extent via CYP3A. Tucatinib was a strong inhibitor of CYP3A (midazolam AUC0–inf increased 5.7-fold), a weak inhibitor of CYP2C8 and P-glycoprotein, and had no impact on CYP2C9-mediated metabolism in humans. Tucatinib was well tolerated, alone and with co-administered drugs.
Conclusion
The potential DDIs identified here may be mitigated by avoiding concomitant use of tucatinib with strong CYP3A inducers, moderate CYP2C8 inducers, CYP3A substrates with a narrow therapeutic window (modifying substrate dose where concomitant use is unavoidable), and strong CYP2C8 inhibitors (decreasing tucatinib dose where concomitant use is unavoidable), or by reducing the dose of P-glycoprotein substrates with a narrow therapeutic window.
Trial Registration
This trial (NCT03723395) was registered on October 29, 2018.
中文翻译：
在健康志愿者中评估 Tucatinib 的安全性和临床相关药物-药物相互作用
背景和目标
Tucatinib 被批准用于治疗人类表皮生长因子受体 2 阳性转移性乳腺癌。了解潜在的药物相互作用 (DDI) 有助于在将 tucatinib 与其他疗法共同给药时确定正确的剂量。本研究的目的是评估 tucatinib 与健康志愿者中代谢酶和转运蛋白之间的 DDI。
方法
A-C 部分评估了伊曲康唑（细胞色素 P450 [CYP] 3A4 抑制剂）、利福平（CYP3A4/CYP2C8 诱导剂）或吉非贝齐（CYP2C8 抑制剂）对单次 300 mg 剂量口服 tucatinib 及其主要药物的药代动力学的影响代谢物，ONT-993。D 部分和 E 部分评估了稳态图卡替尼对瑞格列奈（CYP2C8 底物）、甲苯磺丁脲（CYP2C9 底物）、咪达唑仑（CYP3A4 底物）和地高辛（P-糖蛋白底物）的药代动力学的影响。
结果
从时间 0 外推到无穷大（AUC 0-inf ）的浓度-时间曲线下的 Tucatinib 面积与伊曲康唑和吉非贝齐分别增加了约 1.3 倍和 3.0 倍，与利福平相比减少了 48%，表明 tucatinib 主要代谢通过 CYP2C8，并在较小程度上通过 CYP3A。Tucatinib 是 CYP3A 的强抑制剂（咪达唑仑 AUC 0–inf增加 5.7 倍） ，是 CYP2C8 和 P-糖蛋白的弱抑制剂，并且对 CYP2C9 介导的人体代谢没有影响。Tucatinib 具有良好的耐受性，无论是单独使用还是与共同给药的药物一起使用。
结论
通过避免同时使用 tucatinib 与强 CYP3A 诱导剂、中度 CYP2C8 诱导剂、具有窄治疗窗的 CYP3A 底物（在不可避免地同时使用时修改底物剂量）和强 CYP2C8 抑制剂（减少 tucatinib 剂量，其中伴随使用是不可避免的），或者通过减少具有窄治疗窗的 P-糖蛋白底物的剂量。
试用注册
该试验（NCT03723395）于2018年10月29日注册。
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