Skip to main content

Advertisement

SpringerLink
Log in

Population pharmacokinetics and pharmacogenetics analyses of imatinib in Chinese patients with chronic myeloid leukemia in a real-world situation

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Background

Imatinib is presently the first-line choice for the treatment of chronic myeloid leukemia. However, there are limited real-world data on Chinese patients to support individualized medicine. This work aims to characterize population pharmacokinetics in Chinese patients with chronic myeloid leukemia, investigate the effects of several covariates on imatinib exposure, and provide support for personalized medicine and dose reduction.

Methods

A total of 230 patients with chronic myeloid leukemia were enrolled, and 424 steady-state concentration measurements were taken to perform the population pharmacokinetic analysis and Monte Carlo simulations with Phoenix NLME software. The effects of the demographic, biological, and pharmacogenetic (ten SNP corresponding to CYP3A4, CYP3A5, ABCB1, ABCG2, SCL22A1 and POR) covariates on clearance were evaluated.

Results

A one-compartmental model best-described imatinib pharmacokinetics. The hemoglobin and the estimated glomerular filtration rate (< 85 mL⋅min−1⋅1.73 m2) were associated with imatinib clearance. The genetic polymorphisms related to pharmacokinetics were not found to have a significant effect on the clearance of imatinib. The final model estimates of parameters are: ka (h−1) = 0.329; Vd/F (L) = 270; CL/F (L⋅h−1) = 7.60.

Conclusions

Key covariates in the study population accounting for variability in imatinib exposure are hemoglobin and the estimated glomerular filtration rate. There is some need for caution when treating patients with moderate-to-severe renal impairment and significant hemoglobin changes.

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
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The datasets analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Cohen MH, Williams G, Johnson JR et al (2002) Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 8(5):935–942

    CAS  PubMed  Google Scholar 

  2. García-Ferrer M, Wojnicz A, Mejía G, Koller D, Abad-Santos F (2019) Utility of therapeutic drug monitoring of imatinib, nilotinib, and dasatinib in chronic myeloid leukemia: a systematic review and meta-analysis. Clin Ther 41(12):22

    Article  Google Scholar 

  3. Hochhaus A, Baccarani M, Silver RT et al (2020) European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia 34(4):966–984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Deininger MW, Shah NP, Altman JK et al (2020) Chronic myeloid leukemia, version 22021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 18(10):1385–1415

    Article  CAS  PubMed  Google Scholar 

  5. Peng B, Lloyd P, Schran H (2005) Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 44(9):879–894

    Article  CAS  PubMed  Google Scholar 

  6. Clarke WA, Chatelut E, Fotoohi AK et al (2021) Therapeutic drug monitoring in oncology: International association of therapeutic drug monitoring and clinical toxicology consensus guidelines for imatinib therapy. Euro J Cancer. 157:428–440

    Article  CAS  Google Scholar 

  7. Picard S, Titier K, Etienne G et al (2007) Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 109(8):3496–3499

    Article  CAS  PubMed  Google Scholar 

  8. Larson RA, Druker BJ, Guilhot F et al (2008) Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111(8):4022–4028

    Article  CAS  PubMed  Google Scholar 

  9. Koren-Michowitz M, Volchek Y, Naparstek E et al (2012) Imatinib plasma trough levels in chronic myeloid leukaemia: results of a multicentre study CSTI571AIL11TGLIVEC. Hematol Oncol 30(4):200–205

    Article  CAS  PubMed  Google Scholar 

  10. Marin D, Bazeos A, Mahon F-X et al (2010) Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 28(14):2381–2388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Guilhot F, Hughes TP, Cortes J et al (2012) Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial. Haematologica 97(5):731–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bonate PL (2005) Recommended reading in population pharmacokinetic pharmacodynamics. Aaps j 7(2):E363–E373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. FDA. FDA Guidance for Industry on "Population Pharmacokinetics". 1999;

  14. Corral Alaejos Á, Zarzuelo Castañeda A, Jiménez Cabrera S, Sánchez-Guijo F, Otero MJ, Pérez-Blanco JS (2021) External Evaluation of Population Pharmacokinetic Models of Imatinib in Adults Diagnosed with Chronic Myeloid Leukaemia. Br J Clin Pharmacol 88(4):1913–1924

    Article  PubMed  Google Scholar 

  15. (NCCN) NCCN. NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia (Version 3.2022). available at http://www.nccn.org/patients. Accessed 27 Jan 2022;

  16. Levey AS, Stevens LA, Schmid CH et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612

    Article  PubMed  PubMed Central  Google Scholar 

  17. Petain A, Kattygnarath D, Azard J et al (2008) Population pharmacokinetics and pharmacogenetics of imatinib in children and adults. Clin Cancer Res 14(21):7102–7109

    Article  CAS  PubMed  Google Scholar 

  18. Wang Q, Jiang ZP, Yu EQ et al (2019) Population pharmacokinetic and pharmacogenetics of imatinib in Chinese patients with chronic myeloid leukemia. Pharmacogenomics 20(4):251–260

    Article  PubMed  Google Scholar 

  19. Eechoute K, Fransson MN, Reyners AK et al (2012) A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients. Clin Cancer Res 18(20):5780–5787

    Article  CAS  PubMed  Google Scholar 

  20. Verheijen RB, Yu H, Schellens JHM, Beijnen JH, Steeghs N, Huitema ADR (2017) practical recommendations for therapeutic drug monitoring of kinase inhibitors in oncology. Clin Pharmacol Ther 102(5):765–776

    Article  PubMed  PubMed Central  Google Scholar 

  21. Widmer N, Bardin C, Chatelut E et al (2014) Review of therapeutic drug monitoring of anticancer drugs part two–targeted therapies. Eur J Cancer 50(12):2020–2036

    Article  CAS  PubMed  Google Scholar 

  22. Yu H, Steeghs N, Nijenhuis CM, Schellens JH, Beijnen JH, Huitema AD (2014) Practical guidelines for therapeutic drug monitoring of anticancer tyrosine kinase inhibitors: focus on the pharmacokinetic targets. Clin Pharmacokinet 53(4):305–325

    Article  CAS  PubMed  Google Scholar 

  23. Widmer N, Decosterd LA, Csajka C et al (2006) Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein. Br J Clin Pharmacol 62(1):97–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Adeagbo BA, Olugbade TA, Durosinmi MA, Bolarinwa RA, Ogungbenro K, Bolaji OO (2017) Population Pharmacokinetics of imatinib in nigerians with chronic myeloid leukemia: clinical implications for dosing and resistance. J Clin Pharmacol 57(12):1554–1563

    Article  CAS  PubMed  Google Scholar 

  25. Shriyan B, Mehta P, Patil A et al (2022) Role of ADME gene polymorphisms on imatinib disposition: results from a population pharmacokinetic study in chronic myeloid leukaemia. Eur J Clin Pharmacol 78(8):1321–1330

    Article  CAS  PubMed  Google Scholar 

  26. Di Paolo A, Polillo M, Capecchi M et al (2014) The c480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia. Pharmacogenomics J 14(4):328–335

    Article  PubMed  Google Scholar 

  27. Golabchifar AA, Rezaee S, Dinan NM, Kebriaeezadeh A, Rouini MR (2016) Population pharmacokinetic analysis of the oral absorption process and explaining intra-subject variability in plasma exposures of imatinib in healthy volunteers. Eur J Drug Metab Pharmacokinet 41(5):527–539

    Article  CAS  PubMed  Google Scholar 

  28. Renard D, Bouillon T, Zhou P, Flesch G, Quinn D (2015) Pharmacokinetic interactions among imatinib, bosentan and sildenafil, and their clinical implications in severe pulmonary arterial hypertension. Br J Clin Pharmacol 80(1):75–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schmidli H, Peng B, Riviere GJ et al (2005) Population pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia: results of a phase III study. Br J Clin Pharmacol 60(1):35–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Judson I, Ma P, Peng B et al (2005) Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacokinetic study over time EORTC soft tissue and bone sarcoma group. Cancer Chemother Pharmacol 55(4):379–386

    Article  CAS  PubMed  Google Scholar 

  31. Kretz O, Weiss HM, Schumacher MM, Gross G (2004) In vitro blood distribution and plasma protein binding of the tyrosine kinase inhibitor imatinib and its active metabolite, CGP74588, in rat, mouse, dog, monkey, healthy humans and patients with acute lymphatic leukaemia. Br J Clin Pharmacol 58(2):212–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Prenen H, Guetens G, De Boeck G, Highley M, van Oosterom AT, de Bruijn EA (2006) Everolimus alters imatinib blood partition in favour of the erythrocyte. J Pharm Pharmacol 58(8):1063–1066

    Article  CAS  PubMed  Google Scholar 

  33. Gibbons J, Egorin MJ, Ramanathan RK et al (2008) Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 26(4):570–576

    Article  CAS  PubMed  Google Scholar 

  34. Delbaldo C, Chatelut E, Ré M et al (2006) Pharmacokinetic-pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors. Clin Can Res 12(20 Pt 1):6073–6078

    Article  CAS  Google Scholar 

  35. Demetri GD, Wang Y, Wehrle E et al (2009) Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol 27(19):3141–3147

    Article  CAS  PubMed  Google Scholar 

  36. Yeung CK, Shen DD, Thummel KE, Himmelfarb J (2014) Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport. Kidney Int 85(3):522–528

    Article  CAS  PubMed  Google Scholar 

  37. Lalande L, Charpiat B, Leboucher G, Tod M (2014) Consequences of renal failure on non-renal clearance of drugs. Clin Pharmacokinet 53(6):521–532

    Article  CAS  PubMed  Google Scholar 

  38. Miners JO, Yang X, Knights KM, Zhang L (2017) The role of the kidney in drug elimination: transport, metabolism, and the impact of kidney disease on drug clearance. Clin Pharmacol Ther 102(3):436–449

    Article  CAS  PubMed  Google Scholar 

  39. Menon-Andersen D, Mondick JT, Jayaraman B et al (2009) Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults. Cancer Chemother Pharmacol 63(2):229–238

    Article  CAS  PubMed  Google Scholar 

  40. Ansari M, Kalantary-Khandani B, Pardakhty A, Safavi M, Mosavi N, Mohajeri E (2016) Population Pharmacokinetics of Imatinib and its application to the therapeutic drug monitoring: Middle East CML population. Gulf J Oncolog 1(22):26–36

    PubMed  Google Scholar 

  41. Gotta V, Bouchet S, Widmer N et al (2014) Large-scale imatinib dose-concentration-effect study in CML patients under routine care conditions. Leuk Res 38(7):764–772

    Article  CAS  PubMed  Google Scholar 

  42. Dalle Fratte C, Polesel J, Gagno S et al (2023) Impact of ABCG2 and ABCB1 polymorphisms on imatinib plasmatic exposure: an original work and meta-analysis. Int J Mol Sci 24(4):3303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Smith SA, Waters NJ (2019) Pharmacokinetic and Pharmacodynamic considerations for drugs binding to alpha-1-Acid glycoprotein. Pharma Res. https://doi.org/10.1007/s11095-018-2551-x

    Article  Google Scholar 

Download references

Funding

This work was supported by the Beijing Municipal Natural Science Foundation (grant number 7192218).

Author information

Author notes

  1. Shiyu He and Qianhang Shao have contributed equally.

Authors and Affiliations

  1. Department of Pharmacy, Peking University People’s Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China

    Shiyu He, Qianhang Shao, Jinxia Zhao, Jialu Bian, Yinyu Zhao, Xu Hao, Yuanyuan Li, Lei Hu, Boyu Liu & Lin Huang

  2. Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China

    Shiyu He, Jinxia Zhao, Jialu Bian & Yinyu Zhao

  3. Department of Pharmacy, Beijing Children’s Hospital of Capital Medical University, Beijing, China

    Huan He

  4. Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China

    Qian Jiang

Authors
  1. Shiyu He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qianhang Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jinxia Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jialu Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yinyu Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xu Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuanyuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lei Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Boyu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Huan He
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Qian Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LH and QJ made contributions to the conception and design. JZ and JB helped with the acquisition of data. BL performed imatinib quantification in plasma. LH and XH performed the extraction of genomic DNA and genotyping. SH and HH established the population pharmacokinetic model. SH and QS performed the statistical analysis and interpreted the data. SH wrote the manuscript. YL and YZ drew the tables. LH and QJ were involved in revising the manuscript critically for important intellectual content. All authors gave the final approval of the version to be published.

Corresponding authors

Correspondence to Lin Huang or Qian Jiang.

Ethics declarations

Conflict of interest

All authors declare no conflicts of interest.

Ethical approval

This study was conducted following the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the Peking University People’s Hospital (2022PHB095-001).

Consent to participate

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

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 384 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

He, S., Shao, Q., Zhao, J. et al. Population pharmacokinetics and pharmacogenetics analyses of imatinib in Chinese patients with chronic myeloid leukemia in a real-world situation. Cancer Chemother Pharmacol 92, 399–410 (2023). https://doi.org/10.1007/s00280-023-04581-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-023-04581-0

Keywords

Search

Navigation