Clinical Pharmacology and Drug Metabolism, Sumitomo Dainippon Pharma Oncology, Inc., Cambridge, Massachusetts, USA.
Clinical Development, Sumitomo Dainippon Pharma Oncology, Inc., Cambridge, Massachusetts, USA.
Clin Pharmacol Drug Dev. 2021 Aug;10(8):824-839. doi: 10.1002/cpdd.961. Epub 2021 Jun 9.
Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug-drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug-drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration-time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%-141.4%]), intravenous midazolam (118% [94.4%-147.3%]), repaglinide (127% [104.7%-153.3%]), and rosuvastatin (213% [42.5%-1068.3%]) and decreased the area under the plasma concentration-time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%-108.3%]), bupropion (79% [64.6%-97.0%]), and hydroxybupropion (45% [15.7%-129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.
那布卡沙是一种口服活性氧物种生成剂，可被细胞内抗氧化剂烟酰胺腺嘌呤二核苷酸磷酸：醌氧化还原酶 1 生物激活。那布卡沙诱导包括癌症干细胞在内的癌细胞死亡。这项 I 期研究（NCT03411122）评估了那布卡沙对 7 种细胞色素 P450（CYP）酶和乳腺癌耐药蛋白转运体/有机阴离子转运体 3 的药物相互作用潜力。在第 1 期耐受那布卡沙的健康志愿者在第 2 期接受探针药物，在第 3 期接受那布卡沙（240mg 每日 2 次；第 1-11 天）加包含奥美拉唑（CYP2C19）、咖啡因（CYP1A2）、氟比洛芬（CYP2C9）、安非他酮（CYP2B6）、右美沙芬（CYP2D6）、咪达唑仑（CYP3A）（均为口服；第 6 天）、静脉用咪达唑仑（第 7 天）、瑞格列奈（CYP2C8；第 8 天）和罗苏伐他汀（乳腺癌耐药蛋白/有机阴离子转运体 3；第 9 天）的表型混合液。在 30 名入组志愿者中，有 17 名评估了药物相互作用潜力。那布卡沙联合用药使咖啡因（124%[109.0%-141.4%]）、静脉用咪达唑仑（118%[94.4%-147.3%]）、瑞格列奈（127%[104.7%-153.3%]）和罗苏伐他汀（213%[42.5%-1068.3%]）的血浆浓度-时间曲线从 0 时外推至无穷大的曲线下面积增加（几何均数比[90%置信区间]），使右美沙芬（71%[47.1%-108.3%]）、安非他酮（79%[64.6%-97.0%]）和羟基安非他酮（45%[15.7%-129.6%]）的血浆浓度-时间曲线从 0 时外推至无穷大的曲线下面积减少。未报告严重不良事件/死亡。通常，那布卡沙不太可能诱导/抑制药物清除至具有临床意义的程度。
