Eli Lilly and Company, Indianapolis, Indiana, USA.
Covance Early Clinical Development, Madison, Wisconsin, USA.
Clin Pharmacol Ther. 2019 May;105(5):1187-1195. doi: 10.1002/cpt.1296. Epub 2018 Dec 30.
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6, is indicated for metastatic breast cancer treatment. Reversible increases in serum creatinine levels of ~15-40% over baseline have been observed following abemaciclib dosing. This study assessed the in vitro and clinical inhibition of renal transporters by abemaciclib and its metabolites using metformin (a clinically relevant transporter substrate), in a clinical study that quantified glomerular filtration and iohexol clearance. In vitro, abemaciclib inhibited metformin uptake by organic cation transporter 2, multidrug and toxin extrusion (MATE)1, and MATE2-K transporters with a half-maximal inhibitory concentration of 0.4-3.8 μM. Clinically, abemaciclib significantly increased metformin exposure but did not significantly affect measured glomerular filtration rate, serum neutrophil gelatinase-associated lipocalin (NGAL), serum cystatin-C, or the urinary markers of kidney tubular injury, NGAL and kidney injury molecule-1.
阿贝西利是一种细胞周期蛋白依赖性激酶 4 和 6 的抑制剂，用于治疗转移性乳腺癌。在阿贝西利给药后，观察到血清肌酐水平基线上升约 15-40%。本研究使用二甲双胍（一种临床相关的转运体底物）评估了 abemaciclib 及其代谢物对肾脏转运体的体外和临床抑制作用，该研究采用定量肾小球滤过率和碘海醇清除率的临床研究进行。在体外，阿贝西利以半最大抑制浓度 0.4-3.8 μM 抑制有机阳离子转运蛋白 2、多药和毒素外排 (MATE)1 和 MATE2-K 转运体摄取二甲双胍。临床研究表明，阿贝西利显著增加了二甲双胍的暴露量，但对肾小球滤过率、血清中性粒细胞明胶酶相关脂质运载蛋白 (NGAL)、血清胱抑素 C 或肾脏管状损伤的尿标志物，即 NGAL 和肾损伤分子-1 没有显著影响。
