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 Mar;129:414-423. doi: 10.1016/j.phrs.2017.11.006. Epub 2017 Nov 14.
Encorafenib (LGX818) is a promising BRAF inhibitor that has efficacy against metastatic melanoma. To better understand its pharmacokinetics, we studied its interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A. In polarized MDCK-II cells, encorafenib was efficiently transported by canine and human ABCB1 and ABCG2 and by mouse Abcg2. Upon oral administration to wild-type, Abcb1a/1b, Abcg2, and Abcb1a/1b;Abcg2 mice, encorafenib was absorbed very quickly and to very high plasma levels, but without clear changes in oral availability between the strains. Upon oral or intravenous administration, encorafenib brain accumulation was markedly increased in Abcb1a/1b;Abcg2 mice and to a lesser extent in Abcb1a/1b mice. However, absolute brain concentrations and brain-to-plasma ratios remained very low in all strains, indicating intrinsically poor brain penetration of encorafenib. Upon intravenous administration, Abcb1a/1b;Abcg2 mice showed somewhat reduced plasma elimination of encorafenib compared to wild-type mice, and lower accumulation of the drug in the intestinal tract, suggesting a limited role for these transporters in intestinal elimination of the drug. In Cyp3a mice plasma levels of encorafenib were not markedly increased, suggesting a limited impact of Cyp3a on encorafenib oral availability. The low brain penetration of encorafenib might limit its efficacy against malignancies positioned behind a functional blood-brain barrier, but its oral bioavailability and distribution to other tested organs (liver, kidney, spleen, testis) was high.
恩考芬尼（LGX818）是一种有前景的 BRAF 抑制剂，对转移性黑色素瘤有效。为了更好地了解其药代动力学，我们研究了它与多药外排转运蛋白 ABCB1 和 ABCG2 以及多药代谢酶 CYP3A 的相互作用。在极化的 MDCK-II 细胞中，恩考芬尼被犬和人 ABCB1 和 ABCG2 以及小鼠 Abcg2 有效地转运。在野生型、Abcb1a/1b、Abcg2 和 Abcb1a/1b;Abcg2 小鼠口服给药后，恩考芬尼被迅速吸收到非常高的血浆水平，但在不同品系之间口服生物利用度没有明显变化。口服或静脉给予恩考芬尼后，Abcb1a/1b;Abcg2 小鼠的脑中药物积累明显增加，Abcb1a/1b 小鼠的积累程度较低。然而，所有品系的脑内浓度和脑/血浆比仍然非常低，表明恩考芬尼的脑内穿透性很差。静脉给予恩考芬尼后，Abcb1a/1b;Abcg2 小鼠与野生型小鼠相比，血浆中恩考芬尼的消除速度稍慢，肠道中药物的积累也较低，表明这些转运蛋白在肠道中对药物的消除作用有限。Cyp3a 小鼠的恩考芬尼血浆水平没有明显升高，表明 Cyp3A 对恩考芬尼口服生物利用度的影响有限。恩考芬尼的脑内穿透性低可能限制其对位于功能性血脑屏障后面的恶性肿瘤的疗效，但它的口服生物利用度和分布到其他测试器官（肝脏、肾脏、脾脏、睾丸）很高。
