Skip to main content

Advertisement

SpringerLink
Log in

Influences of ABC transporter and CYP3A4/5 genetic polymorphisms on the pharmacokinetics of lenvatinib in Chinese healthy subjects

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

Abstract

Purpose

To investigate whether the CYP3A4/5 and ABC transporter genetic polymorphisms could affect the pharmacokinetics of lenvatinib in Chinese healthy subjects.

Methods

Thirty-two healthy Chinese volunteers were enrolled and took oral administration of 8 mg lenvatinib. Plasma concentration of lenvatinib was determined by UPLC-MS/MS, the CYP3A4*1G, CYP3A5*3, ABCB1 (3435 C>T, 1236 C>T, 2677 G>T/A), ABCG2 (421 C>A, 34 G>A), and ABCC2-24 C>T genotypes were determined by SnapShot Technique.

Results

In ABCB1 3435T carriers (n = 19), AUC0–120h (815.7 (701.9–923.9) ng·h/mL) and AUC0-∞ (843.3 (722.2–977.7) ng·h/mL) were significantly higher than ABCB1 3435CC homozygous subjects (n = 13, 575.3 (513.7–756.9) ng·h/mL and 590.0 (540.5–782.0) ng·h/mL, respectively); on the contrary, the clearance (CL/F) of ABCB1 3435T carriers was significantly lower (9.5 (8.2–11.1) L/h vs. 13.6 (10.4–14.8) L/h). And the Cmax in CYP3A4*1G/*1G allele carrier subjects was higher than *1 carrier (73.4 ng/mL vs. 53.5 (46.1–60.6) ng/mL), but did not reach the level of significantly statistical difference. Genetic polymorphisms of ABCC2, ABCG2, and CYP3A5 could not influence pharmacokinetic parameters of lenvatinib.

Conclusions

This work presented an evidence that the ABCB1 3435 C>T polymorphism could significantly affect the exposure and clearance of lenvatinib. These findings may explain the reasons for the huge inter-individual differences in lenvatinib, and should contribute to clinical individualized treatment.

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
Fig. 2

Similar content being viewed by others

References

  1. Matsui J, Yamamoto Y, Funahashi Y, Tsuruoka A, Watanabe T, Wakabayashi T, Uenaka T, Asada M (2008) E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 122(3):664–671. https://doi.org/10.1002/ijc.23131

    Article  CAS  PubMed  Google Scholar 

  2. Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M (2008) Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res 14(17):5459–5465. https://doi.org/10.1158/1078-0432.CCR-07-5270

    Article  CAS  PubMed  Google Scholar 

  3. Okamoto K, Kodama K, Takase K, Sugi NH, Yamamoto Y, Iwata M, Tsuruoka A (2013) Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett 340(1):97–103. https://doi.org/10.1016/j.canlet.2013.07.007

    Article  CAS  PubMed  Google Scholar 

  4. Okamoto K, Kodama K, Takase K, Nakamoto K, Coffey H, Selvaraj A, Smith PG, Iwata M, Tsuruoka A (2012) Anti-tumor activities of lenvatinib against RET gene fusion driven tumor models. Eur J Cancer 48:94. https://doi.org/10.1016/S0959-8049(12)72105-6

    Article  Google Scholar 

  5. Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22(10):1276–1312. https://doi.org/10.1101/gad.1653708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yamamoto Y, Matsui J, Matsushima T, Obaishi H, Miyazaki K, Nakamura K, Tohyama O, Semba T, Yamaguchi A, Hoshi SS, Mimura F, Haneda T, Fukuda Y, Kamata JI, Takahashi K, Matsukura M, Wakabayashi T, Asada M, Nomoto KI, Watanabe T, Dezso Z, Yoshimatsu K, Funahashi Y, Tsuruoka A (2014) Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell 6:18. https://doi.org/10.1186/2045-824X-6-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Inc E (2015) Lenvima (lenvatinib) capsules, for oral use: US prescribing information. http://www.fda.gov. Accessed 24 February 2015

  8. Lenvatinib in combination with everolimus. Available online: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501070.htm. Accessed on 8 August 2017

  9. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL (2018) Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391(10126):1163–1173. https://doi.org/10.1016/S0140-6736(18)30207-1

    Article  CAS  PubMed  Google Scholar 

  10. Inc BHP (2013) Nexavar (sorafenib) tablets, oral: US prescribing information. http://labeling.bayerhealthcare.com/html/products/pi/Nexavar_PI.pdf. Accessed 16 Jan 2017

  11. Agency EM (2016) Nexavar (sorafenib):EU summary of product characteristics. http://www.ema.europa.eu/. Accessed 7 Feb 2017

  12. (2018) FDA approves lenvatinib for unresectable hepatocellular carcinoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenvatinib-unresectable-hepatocellular-carcinoma. Accessed 16 August 2018

  13. Dubbelman AC, Rosing H, Nijenhuis C, Huitema ADR, Mergui-Roelvink M, Gupta A, Verbel D, Thompson G, Shumaker R, Schellens JHM, Beijnen JH (2015) Pharmacokinetics and excretion of C-14-lenvatinib in patients with advanced solid tumors or lymphomas. Investig New Drugs 33(1):233–240. https://doi.org/10.1007/s10637-014-0181-7

    Article  CAS  Google Scholar 

  14. Dubbelman AC, Rosing H, Thijssen B, Gebretensae A, Lucas L, Chen H, Shumaker R, Schellens JH, Beijnen JH (2012) Development and validation of LC-MS/MS assays for the quantification of E7080 and metabolites in various human biological matrices. J Chromatogr B Anal Technol Biomed Life Sci 887-888:25–34. https://doi.org/10.1016/j.jchromb.2012.01.004

    Article  CAS  Google Scholar 

  15. (2015) Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206947s007lbl.pdf

  16. Shumaker RC, Aluri J, Fan J, Martinez G, Thompson GA, Ren M (2014) Effect of rifampicin on the pharmacokinetics of lenvatinib in healthy adults. Clin Drug Invest 34(9):651–659. https://doi.org/10.1007/s40261-014-0217-y

    Article  CAS  Google Scholar 

  17. Shumaker R, Aluri J, Fan J, Martinez G, Thompson GA, Ren M (2015) Effects of ketoconazole on the pharmacokinetics of lenvatinib (E7080) in healthy participants. Clin Pharm Drug Dev 4(2):155–160. https://doi.org/10.1002/cpdd.140

    Article  CAS  Google Scholar 

  18. Qiu XY, Jiao Z, Zhang M, Zhong LJ, Liang HQ, Ma CL, Zhang L, Zhong MK (2008) Association of MDR1, CYP3A4*18B, and CYP3A5*3 polymorphisms with cyclosporine pharmacokinetics in Chinese renal transplant recipients. Eur J Clin Pharmacol 64(11):1069–1084. https://doi.org/10.1007/s00228-008-0520-8

    Article  CAS  PubMed  Google Scholar 

  19. Fukushima-Uesaka H, Saito Y, Watanabe H, Shiseki K, Saeki M, Nakamura T, Kurose K, Sai K, Komamura K, Ueno K, Kamakura S, Kitakaze M, Hanai S, Nakajima T, Matsumoto K, Saito H, Goto Y, Kimura H, Katoh M, Sugai K, Minami N, Shirao K, Tamura T, Yamamoto N, Minami H, Ohtsu A, Yoshida T, Saijo N, Kitamura Y, Kamatani N, Ozawa S, Sawada J (2004) Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population. Hum Mutat 23(1):100. https://doi.org/10.1002/humu.9210

    Article  PubMed  Google Scholar 

  20. Du J, Yu L, Wang L, Zhang A, Shu A, Xu L, Xu M, Shi Y, Li X, Feng G, Xing Q, He L (2007) Differences in CYP3A41G genotype distribution and haplotypes of CYP3A4, CYP3A5 and CYP3A7 in 3 Chinese populations. Clin Chim Acta 383(1–2):172–174. https://doi.org/10.1016/j.cca.2007.04.027

    Article  CAS  PubMed  Google Scholar 

  21. Zhang W, Yuan J-J, Kan Q-C, Zhang L-R, Chang Y-Z, Wang Z-Y, Li Z-S (2011) Influence of CYP3A5*3 polymorphism and interaction between CYP3A5*3 and CYP3A4*1G polymorphisms on post-operative fentanyl analgesia in Chinese patients undergoing gynaecological surgery. Eur J Anaesthesiol:1. https://doi.org/10.1097/EJA.0b013e3283438b39

  22. Haufroid V (2011) Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCC2 and their impact on drug disposition. Curr Drug Targets 12(5):631–646

    Article  CAS  Google Scholar 

  23. Chen X, Chen D, Yang S, Ma R, Pan Y, Li X, Ma S (2015) Impact of ABCG2 polymorphisms on the clinical outcome of TKIs therapy in Chinese advanced non-small-cell lung cancer patients. Cancer Cell Int 15:43. https://doi.org/10.1186/s12935-015-0191-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lin JH (2007) Transporter-mediated drug interactions: clinical implications and in vitro assessment. Expert Opin Drug Metab Toxicol 3(1):81–92. https://doi.org/10.1517/17425255.3.1.81

    Article  CAS  PubMed  Google Scholar 

  25. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1987) Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A 84(21):7735–7738. https://doi.org/10.1073/pnas.84.21.7735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Robey RW, Polgar O, Deeken J, To KW, Bates SE (2007) ABCG2: determining its relevance in clinical drug resistance. Cancer Metastasis Rev 26(1):39–57. https://doi.org/10.1007/s10555-007-9042-6

    Article  CAS  PubMed  Google Scholar 

  27. Hussein Z, Mizuo H, Hayato S, Namiki M, Shumaker R (2017) Clinical pharmacokinetic and pharmacodynamic profile of lenvatinib, an orally active, small-molecule, multitargeted tyrosine kinase inhibitor. Eur J Drug Metab Pharmacokinet 42(6):903–914. https://doi.org/10.1007/s13318-017-0403-4

    Article  CAS  PubMed  Google Scholar 

  28. Shumaker R, Aluri J, Fan J, Martinez G, Ren M, Chen K (2014) Evaluation of the effects of formulation and food on the pharmacokinetics of lenvatinib (E7080) in healthy volunteers. Int J Clin Pharmacol Ther 52(4):284–291. https://doi.org/10.5414/Cp201937

    Article  CAS  PubMed  Google Scholar 

  29. Koyama N, Saito K, Nishioka Y, Yusa W, Yamamoto N, Yamada Y, Nokihara H, Koizumi F, Nishio K, Tamura T (2014) Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib. BMC Cancer 14:530. https://doi.org/10.1186/1471-2407-14-530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yamada K, Yamamoto N, Yamada Y, Nokihara H, Fujiwara Y, Hirata T, Koizumi F, Nishio K, Koyama N, Tamura T (2011) Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors. Clin Cancer Res 17(8):2528–2537. https://doi.org/10.1158/1078-0432.CCR-10-2638

    Article  CAS  PubMed  Google Scholar 

  31. Takahashi N, Miura M, Scott SA, Kagaya H, Kameoka Y, Tagawa H, Saitoh H, Fujishima N, Yoshioka T, Hirokawa M, Sawada K (2010) Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia. J Hum Genet 55(11):731–737. https://doi.org/10.1038/jhg.2010.98

    Article  CAS  PubMed  Google Scholar 

  32. Tamai T, Hayato S, Hojo S, Suzuki T, Okusaka T, Ikeda K, Kumada H (2017) Dose finding of lenvatinib in subjects with advanced hepatocellular carcinoma based on population pharmacokinetic and exposure-response analyses. J Clin Pharmacol 57(9):1138–1147. https://doi.org/10.1002/jcph.917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gupta A, Jarzab B, Capdevila J, Shumaker R, Hussein Z (2016) Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer. Brit J Clin Pharmacol 81(6):1124–1133. https://doi.org/10.1111/bcp.12907

    Article  CAS  Google Scholar 

  34. Scott LJ (2015) Lenvatinib: first global approval. Drugs 75(5):553–560. https://doi.org/10.1007/s40265-015-0383-0

    Article  CAS  PubMed  Google Scholar 

  35. Zhang W, Chang YZ, Kan QC, Zhang LR, Li ZS, Lu H, Wang ZY, Chu QJ, Zhang J (2010) CYP3A4*1G genetic polymorphism influences CYP3A activity and response to fentanyl in Chinese gynecologic patients. Eur J Clin Pharmacol 66(1):61–66. https://doi.org/10.1007/s00228-009-0726-4

    Article  CAS  PubMed  Google Scholar 

  36. Hu GX, Dai DP, Wang H, Huang XX, Zhou XY, Cai J, Chen H, Cai JP (2017) Systematic screening for CYP3A4 genetic polymorphisms in a Han Chinese population. Pharmacogenomics 18(4):369–379. https://doi.org/10.2217/pgs-2016-0179

    Article  CAS  PubMed  Google Scholar 

  37. Zhang J, Dai Y, Liu Z, Zhang M, Li C, Chen D, Song H (2017) Effect of CYP3A4 and CYP3A5 genetic polymorphisms on the pharmacokinetics of sirolimus in healthy Chinese volunteers. Ther Drug Monit 39(4):406–411. https://doi.org/10.1097/FTD.0000000000000415

    Article  CAS  PubMed  Google Scholar 

  38. Wang D, Johnson AD, Papp AC, Kroetz DL, Sadée W (2005) Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics 15(10):693–704. https://doi.org/10.1097/01.fpc.0000178311.02878.83

    Article  CAS  PubMed  Google Scholar 

  39. Harivenkatesh N, Kumar L, Bakhshi S, Sharma A, Kabra M, Velpandian T, Gogia A, Shastri SS, Biswas NR, Gupta YK (2017) Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and therapeutic response of imatinib in newly diagnosed patients with chronic myeloid leukemia. Pharmacol Res 120:138–145. https://doi.org/10.1016/j.phrs.2017.03.011

    Article  CAS  PubMed  Google Scholar 

  40. Yamakawa Y, Hamada A, Nakashima R, Yuki M, Hirayama C, Kawaguchi T, Saito H (2011) Association of genetic polymorphisms in the influx transporter SLCO1B3 and the efflux transporter ABCB1 with imatinib pharmacokinetics in patients with chronic myeloid leukemia. Ther Drug Monit 33(2):244–250. https://doi.org/10.1097/FTD.0b013e31820beb02

    Article  CAS  PubMed  Google Scholar 

  41. Boss DS, Glen H, Beijnen JH, Keesen M, Morrison R, Tait B, Copalu W, Mazur A, Wanders J, O'Brien JP, Schellens JH, Evans TR (2012) A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br J Cancer 106(10):1598–1604. https://doi.org/10.1038/bjc.2012.154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by a Fundamental Research Fund (No. 2632018PT02) for the Central Universities and “Double First-Class” initiative Innovation team project (No. CPU2018GY29) of China Pharmaceutical University.

Author information

Authors and Affiliations

  1. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, #639 Longmian Avenue, Jiangning District, Nanjing, 211198, China

    Jiaming Li, Xiaoqian Wang, Chen Ning, Zhaoyu Wang, Yao Wang, Siliang Zhang, Yang Lu, Yongjie Zhang, Xijing Chen & Di Zhao

  2. School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China

    Ming Zheng

  3. National Experimental Teaching Demonstration Center of Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China

    Ning Li

Authors
  1. Jiaming Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoqian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chen Ning
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhaoyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Siliang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yongjie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ning Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xijing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Di Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Di Zhao and Xijing Chen participated in designing and guiding this study. Jiaming Li, Xiaoqian Wang, Chen Ning, Yao Wang, Zhaoyu Wang, Ming Zheng, and Siliang Zhang completed the whole experiment. Jiaming Li and Di Zhao were responsible for the data statistics. Jiaming Li wrote the first draft of this article. Di Zhao, Xijing Chen, Yongjie Zhang, Yang Lu, and Ning Li helped to put forward academic suggestions and revise the manuscript.

Corresponding authors

Correspondence to Xijing Chen or Di Zhao.

Ethics declarations

This study was approved by the relevant institutional review board of the Lilairuide Clinic (Nanjing, China).

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

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

Electronic supplementary material

ESM 1

(DOCX 31 kb).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, J., Wang, X., Ning, C. et al. Influences of ABC transporter and CYP3A4/5 genetic polymorphisms on the pharmacokinetics of lenvatinib in Chinese healthy subjects. Eur J Clin Pharmacol 76, 1125–1133 (2020). https://doi.org/10.1007/s00228-020-02879-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-020-02879-z

Keywords

Search

Navigation