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Medical Oncology

, 36:55 | Cite as

Influence of ABCB1 polymorphisms on the pharmacokinetics and toxicity of lenalidomide in patients with multiple myeloma

  • Takahiro KobayashiEmail author
  • Masatomo Miura
  • Maiko Abumiya
  • Yumiko Akamine
  • Fumiko Ito
  • Naoto Takahashi
Original Paper
  • 62 Downloads

Abstract

Individual diversity in plasma concentrations of lenalidomide occurs despite dosage modifications based on creatinine clearance (CCr), which can lead to unexpected toxicity. We have previously identified a cutoff value of area under the concentration–time curve (AUC0–24) for lenalidomide to avoid severe toxicity. Here, we investigated the association between ABCB1 polymorphisms and pharmacokinetics of lenalidomide in patients with multiple myeloma (MM) treated with lenalidomide and dexamethasone. Plasma concentrations of lenalidomide were analyzed using liquid chromatography–tandem mass spectrometry. Genotyping for ABCB1 1236C>T, 2677G>A/T, and 3435C>T polymorphisms was performed, and the effects of ABCB1 polymorphisms on AUC0–24 for lenalidomide were compared in 36 patients with MM who were administered lenalidomide according to the drug label based on CCr. Genotyping analysis showed that although there were no differences in AUC0–24 in 1236C>T and 2677G>A/T polymorphisms. AUC0–24 was significantly higher in patients with the T allele of 3435C>T (n = 15) than in those without (n = 21) (median 6324.6 ng h/mL vs. 2857.4 ng h/mL, p = 0.028). The AUC0–24 value exceeded the aforementioned cutoff value in 95% of the patients with the T allele of 3435C>T but in 60% with C/C genotype (p = 0.013). Multivariate logistic analysis confirmed the significance of T allele of ABCB1 3435C>T as a factor due to which the AUC0–24 cutoff value was exceeded (hazard ratio of 15.0, p = 0.019). We show that lenalidomide pharmacokinetics is influenced by the ABCB1 3435C>T polymorphism, which could be useful to individualize dosage design and reduce unexpected toxicity.

Keywords

Multiple myeloma Lenalidomide Pharmacokinetics P-glycoprotein ABCB1 polymorphisms 

Notes

Funding

This work was supported by Japan Society for the Promotion of Science (KAKENHI Grant Number 26461414 for Scientific Research to N.T.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the Ethics Committee of Akita University School of Medicine (No. 905) and with the 1964 Helsinki Declaration.

Supplementary material

12032_2019_1280_MOESM1_ESM.docx (18 kb)
Supplementary material 1 (DOCX 18 kb)
12032_2019_1280_MOESM2_ESM.docx (16 kb)
Supplementary material 2 (DOCX 16 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Hematology, Nephrology, and RheumatologyAkita University Graduate School of MedicineAkita CityJapan
  2. 2.Department of PharmacyAkita University HospitalAkitaJapan

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