Effects of ABCB1 and ABCG2 polymorphisms on the pharmacokinetics of abemaciclib
Effects of ABCB1 and ABCG2 polymorphisms on the pharmacokinetics of abemaciclib
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DOI：
10.1007/s00228-022-03331-0
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发表时间：
2021-09
影响因子：
2.9
通讯作者：
Akimitsu Maeda;Hitoshi Ando;Kei Irie;Naoya Hashimoto;Jun‐ichi Morishige;Shoji Fukushima;Akira Okada;H. Ebi;Masahide Matsuzaki;Hiroji Iwata;M. Sawaki
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作者：
Akimitsu Maeda;Hitoshi Ando;Kei Irie;Naoya Hashimoto;Jun‐ichi Morishige;Shoji Fukushima;Akira Okada;H. Ebi;Masahide Matsuzaki;Hiroji Iwata;M. Sawaki
使用CDK 4/6抑制剂abemaciclib后的不良事件具有剂量依赖性。然而，其药代动力学因个体而异。据报道，Abemaciclib通过P-糖蛋白和乳腺癌耐药蛋白转运。因此，我们评估ABCB 1和ABCG 2多态性是否是abemaciclib的药代动力学预测因素。（150 mg，每天两次），持续2周，以确定abemaciclib浓度、不良事件、ABCB 11236 T > C、2677 G> T/A、3435 C> T和ABCG 2421 C> A基因多态性。对于ABCB 12677 G> T/A多态性，纯合子组（TT + AT）的abemaciclib浓度往往高于野生型+杂合子组（GG + GA + GT）（中位数[范围]，222.8 [80.5-295.8] ng/mL vs. 113.5 [23.6-355.2] ng/mL，P= 0.09），此外，ABCB 1 2677 G> T/A纯合子组在4周内abemaciclib停药或剂量减少的趋势高于野生型+杂合子组（比值比，4.22; 95%置信区间，0.86-20.7;P= 0.08）。ABCB 11236 T > C、3435 C> T和ABCG 2421 C> A多态性与abemaciclib的药物浓度、不良反应无显著相关性。
PurposeAdverse events after the use of the CDK4/6 inhibitor abemaciclib are dose-dependent. However, its pharmacokinetics varies among individuals. Abemaciclib is reportedly transported by P-glycoprotein and breast cancer resistance protein. Therefore, we evaluated whetherABCB1andABCG2polymorphisms are pharmacokinetic predictive factors of abemaciclib.MethodsA total of 45 patients with breast cancer taking abemaciclib (150 mg twice per day) for 2 weeks were evaluated to determine the associations among abemaciclib concentration; adverse events; andABCB11236 T > C, 2677G > T/A, 3435C > T, andABCG2421C > A gene polymorphisms.ResultsThe trough concentration of abemaciclib was significantly higher in the group with grade 2 or greater neutropenia and thrombocytopenia than in those with grades 0 or 1. ForABCB12677G > T/A polymorphisms, the concentration of abemaciclib tended to be higher in the homozygous group (TT + AT) than in the wild-type + heterozygous group (GG + GA + GT) (median [range], 222.8 [80.5–295.8] ng/mL vs. 113.5 [23.6–355.2] ng/mL,P= 0.09), Moreover, the ABCB1 2677G > T/A homozygous group had a higher tendency of abemaciclib withdrawal or dose reduction within 4 weeks than the wild-type + heterozygous group (odds ratio, 4.22; 95% confidence interval, 0.86–20.7;P= 0.08). No significant association was observed among abemaciclib concentration; adverse reactions; andABCB11236 T > C, 3435C > T, andABCG2421C > A polymorphisms.ConclusionABCB12677G > T/A polymorphism might be a predictor of the pharmacokinetics and tolerability of abemaciclib.