Skip to main content

Advertisement

SpringerLink
Log in

Effects of ABCB1 and ABCG2 polymorphisms on the pharmacokinetics of abemaciclib

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Adverse 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 whether ABCB1 and ABCG2 polymorphisms are pharmacokinetic predictive factors of abemaciclib.

Methods

A 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; and ABCB1 1236 T > C, 2677G > T/A, 3435C > T, and ABCG2 421C > A gene polymorphisms.

Results

The 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. For ABCB1 2677G > 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; and ABCB1 1236 T > C, 3435C > T, and ABCG2 421C > A polymorphisms.

Conclusion

ABCB1 2677G > T/A polymorphism might be a predictor of the pharmacokinetics and tolerability of abemaciclib.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The datasets during and/or analyzed during the present study are available from the corresponding author upon reasonable request.

References

  1. Johnston S, Martin M, Di Leo A, Im SA, Awada A, Forrester T, Frenzel M, Hardebeck MC, Cox J, Barriga S, Toi M, Iwata H, Goetz MP (2019) MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 5:5. https://doi.org/10.1038/s41523-018-0097-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A (2017) MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2-advanced breast cancer who had progressed while receiving endocrine therapy. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 35(25):2875–2884. https://doi.org/10.1200/jco.2017.73.7585

    Article  CAS  Google Scholar 

  3. Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Tredan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A (2017) MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 35(32):3638–3646. https://doi.org/10.1200/jco.2017.75.6155

    Article  CAS  Google Scholar 

  4. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Conte P, Lu Y, Barriga S, Hurt K, Frenzel M, Johnston S, Llombart-Cussac A (2020) The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial. JAMA Oncol 6(1):116–124. https://doi.org/10.1001/jamaoncol.2019.4782

    Article  PubMed  Google Scholar 

  5. Fujiwara Y, Tamura K, Kondo S, Tanabe Y, Iwasa S, Shimomura A, Kitano S, Ogasawara K, Turner PK, Mori J, Asou H, Chan EM, Yamamoto N (2016) Phase 1 study of abemaciclib, an inhibitor of CDK 4 and 6, as a single agent for Japanese patients with advanced cancer. Cancer Chemother Pharmacol 78(2):281–288. https://doi.org/10.1007/s00280-016-3085-8

    Article  CAS  PubMed  Google Scholar 

  6. Tate SC, Sykes AK, Kulanthaivel P, Chan EM, Turner PK, Cronier DM (2018) A population pharmacokinetic and pharmacodynamic analysis of abemaciclib in a phase I clinical trial in cancer patients. Clin Pharmacokinet 57(3):335–344. https://doi.org/10.1007/s40262-017-0559-8

    Article  CAS  PubMed  Google Scholar 

  7. Maeda A, Irie K, Hashimoto N, Fukushima S, Ando H, Okada A, Ebi H, Kajita M, Iwata H, Sawaki M (2021) Serum concentration of the CKD4/6 inhibitor abemaciclib, but not of creatinine, strongly predicts hematological adverse events in patients with breast cancer: a preliminary report. Invest New Drugs 39(1):272–277. https://doi.org/10.1007/s10637-020-00994-3

    Article  CAS  PubMed  Google Scholar 

  8. Posada MM, Morse BL, Turner PK, Kulanthaivel P, Hall SD, Dickinson GL (2020) Predicting clinical effects of CYP3A4 modulators on abemaciclib and active metabolites exposure using physiologically based pharmacokinetic modeling. J Clin Pharmacol 60(7):915–930. https://doi.org/10.1002/jcph.1584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE, Altman RB (2011) Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics 21(3):152–161. https://doi.org/10.1097/FPC.0b013e3283385a1c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wacher VJ, Wu CY, Benet LZ (1995) Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 13(3):129–134. https://doi.org/10.1002/mc.2940130302

    Article  CAS  PubMed  Google Scholar 

  11. Wu T, Chen Z, To KKW, Fang X, Wang F, Cheng B, Fu L (2017) Effect of abemaciclib (LY2835219) on enhancement of chemotherapeutic agents in ABCB1 and ABCG2 overexpressing cells in vitro and in vivo. Biochem Pharmacol 124:29–42. https://doi.org/10.1016/j.bcp.2016.10.015

    Article  CAS  PubMed  Google Scholar 

  12. Martínez-Chávez A, Loos NHC, Lebre MC, Tibben MM, Rosing H, Beijnen JH, Schinkel AH (2021) ABCB1 and ABCG2 limit brain penetration and together with CYP3A4, total plasma exposure of abemaciclib and its active metabolites. Pharmacol Res 105954. https://doi.org/10.1016/j.phrs.2021.105954

  13. Han LW, Gao C, Mao Q (2018) An update on expression and function of P-gp/ABCB1 and BCRP/ABCG2 in the placenta and fetus. Expert Opin Drug Metab Toxicol 14(8):817–829. https://doi.org/10.1080/17425255.2018.1499726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hsin CH, Stoffel MS, Gazzaz M, Schaeffeler E, Schwab M, Fuhr U, Taubert M (2020) Combinations of common SNPs of the transporter gene ABCB1 influence apparent bioavailability, but not renal elimination of oral digoxin. Sci Rep 10(1):12457. https://doi.org/10.1038/s41598-020-69326-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Leslie EM, Deeley RG, Cole SP (2005) Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol 204(3):216–237. https://doi.org/10.1016/j.taap.2004.10.012

    Article  CAS  PubMed  Google Scholar 

  16. Ieiri I (2012) Functional significance of genetic polymorphisms in P-glycoprotein (MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2). Drug Metab Pharmacokinet 27(1):85–105. https://doi.org/10.2133/dmpk.dmpk-11-rv-098

    Article  CAS  PubMed  Google Scholar 

  17. Lal S, Wong ZW, Sandanaraj E, Xiang X, Ang PC, Lee EJ, Chowbay B (2008) Influence of ABCB1 and ABCG2 polymorphisms on doxorubicin disposition in Asian breast cancer patients. Cancer Sci 99(4):816–823. https://doi.org/10.1111/j.1349-7006.2008.00744.x

    Article  CAS  PubMed  Google Scholar 

  18. Kim HJ, Im SA, Keam B, Ham HS, Lee KH, Kim TY, Kim YJ, Oh DY, Kim JH, Han W, Jang IJ, Kim TY, Park IA, Noh DY (2015) ABCB1 polymorphism as prognostic factor in breast cancer patients treated with docetaxel and doxorubicin neoadjuvant chemotherapy. Cancer Sci 106(1):86–93. https://doi.org/10.1111/cas.12560

    Article  CAS  PubMed  Google Scholar 

  19. Zhou SF, Xue CC, Yu XQ, Li C, Wang G (2007) Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit 29(6):687–710. https://doi.org/10.1097/FTD.0b013e31815c16f5

    Article  CAS  PubMed  Google Scholar 

  20. Glaeser H (2011) Importance of P-glycoprotein for drug-drug interactions. Handb Exp Pharmacol 201:285–297. https://doi.org/10.1007/978-3-642-14541-4_7

    Article  CAS  Google Scholar 

  21. Drug Development and Drug Interactions (2020) | Table of Substrates, Inhibitors and Inducers. In: ed. U.S. Food and Drug Administration

  22. Wickremsinhe ER, Lee LB (2021) Quantification of abemaciclib and metabolites: evolution of bioanalytical methods supporting a novel oncolytic agent. Bioanalysis 13(9):711–724. https://doi.org/10.4155/bio-2021-0039

    Article  CAS  PubMed  Google Scholar 

  23. Kanda Y (2013) Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 48(3):452–458. https://doi.org/10.1038/bmt.2012.244

    Article  CAS  PubMed  Google Scholar 

  24. Greenblatt DJ, Allen MD, Harmatz JS, Shader RI (1980) Diazepam disposition determinants. Clin Pharmacol Ther 27(3):301–312. https://doi.org/10.1038/clpt.1980.40

    Article  CAS  PubMed  Google Scholar 

  25. Fasanmade AA, Adedokun OJ, Olson A, Strauss R, Davis HM (2010) Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis. Int J Clin Pharmacol Ther 48(5):297–308. https://doi.org/10.5414/cpp48297

    Article  CAS  PubMed  Google Scholar 

  26. Yamasaki K, Chuang VT, Maruyama T (1830) Otagiri M (2013) Albumin-drug interaction and its clinical implication. Biochem Biophys Acta 12:5435–5443. https://doi.org/10.1016/j.bbagen.2013.05.005

    Article  CAS  Google Scholar 

  27. Modi ND, Abuhelwa AY, Badaoui S, Shaw E, Shankaran K, McKinnon RA, Rowland A, Sorich MJ, Hopkins AM (2021) Prediction of severe neutropenia and diarrhoea in breast cancer patients treated with abemaciclib. Breast (Edinburgh, Scotland) 58:57–62. https://doi.org/10.1016/j.breast.2021.04.003

    Article  Google Scholar 

  28. Iwata H, Umeyama Y, Liu Y, Zhang Z, Schnell P, Mori Y, Fletcher O, Marshall JC, Johnson JG, Wood LS, Toi M, Finn RS, Turner NC, Bartlett CH, Cristofanilli M (2021) Evaluation of the association of polymorphisms with palbociclib-induced neutropenia: pharmacogenetic analysis of PALOMA-2/-3. Oncologist 26(7):e1143–e1155. https://doi.org/10.1002/onco.13811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vivona D, Lima LT, Rodrigues AC, Bueno CT, Alcantara GK, Barros LS, Hungria VT, Chiattone CS, Chauffaille MD, Guerra‑Shinohara EM (2014) ABCB1 haplotypes are associated with P-gp activity and affect a major molecular response in chronic myeloid leukemia patients treated with a standard dose of imatinib. Oncol Lett 7(4):1313–1319. https://doi.org/10.3892/ol.2014.1857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Keskitalo JE, Kurkinen KJ, Neuvoneni PJ, Niemi M (2008) ABCB1 haplotypes differentially affect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin. Clin Pharmacol Ther 84(4):457–461. https://doi.org/10.1038/clpt.2008.25

    Article  CAS  PubMed  Google Scholar 

  31. Chowbay B, Cumaraswamy S, Cheung YB, Zhou Q, Lee EJ (2003) Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics 13(2):89–95. https://doi.org/10.1097/00008571-200302000-00005

    Article  CAS  PubMed  Google Scholar 

  32. Lamba JK, Lin YS, Thummel K, Daly A, Watkins PB, Strom S, Zhang J, Schuetz EG (2002) Common allelic variants of cytochrome P4503A4 and their prevalence in different populations. Pharmacogenetics 12(2):121–132. https://doi.org/10.1097/00008571-200203000-00006

    Article  CAS  PubMed  Google Scholar 

  33. Yamamoto T, Nagafuchi N, Ozeki T, Kubota T, Ishikawa H, Ogawa S, Yamada Y, Hirai H, Iga T (2003) CYP3A4*18: it is not rare allele in Japanese population. Drug Metab Pharmacokinet 18(4):267–268. https://doi.org/10.2133/dmpk.18.267

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the patients for their participation in this study. We are grateful to Naomi Nagai (Musashino University) for helpful discussions and insightful comments on our manuscript.

Funding

This study was funded by Aichi Cancer Research Foundation.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan

    Akimitsu Maeda, Naoya Hashimoto & Masahide Matsuzaki

  2. Department of Cellular and Molecular Function Analysis, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan

    Hitoshi Ando & Jun-ichi Morishige

  3. Department of Pharmaceutics, Faculty of Pharmaceutical Science, Kobe Gakuin University, 1−1−3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan

    Kei Irie & Shoji Fukushima

  4. Department of Pharmacy, Kobe City Hospital Organization, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minami-machi, Chuo-ku, Kobe, 650-0047, Japan

    Kei Irie

  5. Department of Regulatory Science, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi , Nishitokyo City, 202-8585, Japan

    Akira Okada

  6. Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan

    Hiromichi Ebi

  7. Department of Breast Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan

    Hiroji Iwata & Masataka Sawaki

Authors
  1. Akimitsu Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hitoshi Ando
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kei Irie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Naoya Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun-ichi Morishige
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shoji Fukushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Akira Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiromichi Ebi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masahide Matsuzaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiroji Iwata
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masataka Sawaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation was performed by Akimitsu M. Data collection was performed by Akimitsu M, Naoya H, Hiroji I, and Masataka S. Analysis was performed by Hitoshi A, Kei I, Jun-ichi M, Shoji F, and Hiromichi E. The first draft of the manuscript was written by Akimitsu M, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Akimitsu Maeda.

Ethics declarations

Ethics approval

All procedures performed in this study that involved human participants were conducted in accordance with the standards of the Ethics Committee of Aichi Cancer Center Hospital (No.: 2018–2-27) and the Declaration of Helsinki.

Consent to participate

Written informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable.

Competing interests

Hitoshi Ando had received a grant from Eli Lilly Japan. Hiroji Iwata had received honorarium for educational lectures and advisor from Eli Lilly Japan. All other authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 17 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Maeda, A., Ando, H., Irie, K. et al. Effects of ABCB1 and ABCG2 polymorphisms on the pharmacokinetics of abemaciclib. Eur J Clin Pharmacol 78, 1239–1247 (2022). https://doi.org/10.1007/s00228-022-03331-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-022-03331-0

Keywords

Search

Navigation