The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Universiteitsweg 99, 3584 CG, Utrecht, the Netherlands.
Pharmacol Res. 2018 Nov;137:47-55. doi: 10.1016/j.phrs.2018.09.020. Epub 2018 Sep 22.
Brigatinib is an FDA-approved oral anaplastic lymphoma kinase (ALK) inhibitor for treatment of metastatic non-small cell lung cancer (NSCLC). Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3 A in plasma pharmacokinetics and tissue distribution of brigatinib. In vitro, brigatinib was exceptionally well transported by human ABCB1 and mouse Abcg2, and efficiently by human ABCG2. Following oral brigatinib administration (10 mg/kg), brain accumulation was dramatically increased in Abcb1a/1b (19.3-fold) and Abcb1a/1b;Abcg2(41.8-fold), but not in single Abcg2 mice compared to wild-type mice. Brigatinib testis accumulation showed qualitatively similar behavior. mAbcb1a/1b and mAbcg2 together restricted systemic exposure of brigatinib: with both systems absent oral availability increased 1.9-fold. Coadministration of elacridar, an ABCB1/ABCG2 inhibitor, caused a pronounced increase (36-fold) in brain-to-plasma ratios of brigatinib, approaching the levels seen in Abcb1a/1b;Abcg2 mice. Unexpectedly, lethal toxicity of oral brigatinib was observed in mice with genetic knockout or pharmacological inhibition of mAbcb1a/1b and mAbcg2, indicating a pronounced protective role for these transporters. In Cyp3a mice, brigatinib plasma exposure increased 1.3-fold, and was subsequently 1.8-fold reduced by transgenic overexpression of human CYP3 A4 in liver and intestine. The relative tissue distribution of brigatinib, however, remained unaltered. ABCB1 and ABCG2 thus limit brain accumulation, toxicity, and systemic exposure of brigatinib, whereas CYP3 A also markedly restricts its oral availability. Unexpected toxicities should therefore be carefully monitored when brigatinib is coadministered with ABCB1/ABCG2 inhibitors in patients. Collectively, these insights may support the clinical application of brigatinib.
布加替尼是一种经美国食品药品监督管理局批准的用于治疗转移性非小细胞肺癌的间变性淋巴瘤激酶（ALK）抑制剂。我们利用基因修饰的小鼠模型研究了多药外排转运蛋白 ABCB1 和 ABCG2，以及多药代谢酶 CYP3A 在布加替尼的血浆药代动力学和组织分布中的作用。体外实验表明，布加替尼能被人源 ABCB1 和鼠源 Abcg2 高效转运，也能被人源 ABCG2 有效转运。口服布加替尼（10mg/kg）后，与野生型小鼠相比，Abcb1a/1b（19.3 倍）和 Abcb1a/1b;Abcg2（41.8 倍）小鼠的脑内药物蓄积显著增加，但 Abcg2 单基因敲除小鼠则不然。布加替尼在睾丸中的蓄积也表现出相似的定性行为。mAbcb1a/1b 和 mAbcg2 共同限制了布加替尼的全身暴露：当这两个系统都不存在时，口服生物利用度增加了 1.9 倍。联合应用 ABCB1/ABCG2 抑制剂 elacridar 可使布加替尼的脑-血浆比显著增加（36 倍），接近 Abcb1a/1b;Abcg2 小鼠中的水平。出乎意料的是，在 mAbcb1a/1b 和 mAbcg2 基因敲除或药理学抑制的小鼠中观察到口服布加替尼的致命毒性，表明这些转运蛋白具有明显的保护作用。在 Cyp3a 小鼠中，布加替尼的血浆暴露量增加了 1.3 倍，而在肝脏和肠道中过表达人源 CYP3A4 后，其暴露量则减少了 1.8 倍。然而，布加替尼的相对组织分布仍未改变。因此，ABCB1 和 ABCG2 限制了布加替尼的脑内蓄积、毒性和全身暴露，而 CYP3A 也显著限制了其口服生物利用度。因此，在患者中联合应用 ABCB1/ABCG2 抑制剂时，应密切监测布加替尼的潜在毒性。综上所述，这些发现可能为布加替尼的临床应用提供支持。
