Effects of ABCB1 and ABCG2 Polymorphisms on the Pharmacokinetics of Abemaciclib Metabolites (M2, M20, M18)

Background/Aim: Abemaciclib, an oral anticancer drug used in the treatment of breast cancer, is metabolised to its active forms - M2, M20 and M18; these forms have a potency similar to that of the parent drug. Abemaciclib and its active metabolites are reportedly transported by P-glycoprotein and breast cancer resistance protein (BCRP). We previously reported that the ABCB1 2677G>T/A homozygous type is associated with a higher abemaciclib concentration leading to treatment withdrawal and/or dose reduction. However, the pharmacokinetics of its metabolites have not been investigated. The purpose of the present study was to evaluate the effects of ABCB1 and ABCG2 polymorphisms on the pharmacokinetics of the abemaciclib metabolites M2, M20 and M18. Patients and Methods: We evaluated 40 patients with breast cancer who received 150 mg abemaciclib twice per day for 2 weeks at the Aichi Cancer Center Hospital, Japan. Peak areas (arbitrary unit) of abemaciclib metabolites were measured using liquid chromatography tandem with mass spectrometry and compared between ABCB1 1236T>C, 2677G>T/A, 3435C>T and ABCG2 421C>A gene polymorphisms. Results: For ABCB1 2677G>T/A polymorphisms, exposure doses for the abemaciclib metabolites M2 and M20 were higher in the homozygous (TT + AT) group than in the wild-type and heterozygous (GG + GA + GT) groups (p=0.09 and p=0.06, respectively). No significant association was observed between abemaciclib metabolites and ABCB1 1236T>C, ABCB1 3435C>T and ABCG2 421C>A polymorphisms. Conclusion: The ABCB1 2677G>T/A polymorphism may influence tolerance to abemaciclib in breast cancer patients by affecting the pharmacokinetics of the agent and its active metabolites.

Automated summary

The study evaluated the effects of ABCB1 and ABCG2 gene polymorphisms on the pharmacokinetics of abemaciclib metabolites M2, M20, and M18. The results suggest that the ABCB1 2677G>T/A polymorphism may influence tolerance to abemaciclib in breast cancer patients by affecting the pharmacokinetics of the drug and its active metabolites.