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Effect of Cytochrome P450 and ABCB1 Polymorphisms on Imatinib Pharmacokinetics After Single-Dose Administration to Healthy Subjects

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Abstract

Background

Validated genomic biomarkers for oncological drugs are expanding to improve targeted therapies. Pharmacogenetics research focusing on the mechanisms underlying imatinib suboptimal response might help to explain the different treatment outcomes and drug safety profiles.

Objective

To investigate whether polymorphisms in genes encoding cytochrome P450 (CYP) enzymes and ABCB1 transporter affect imatinib pharmacokinetic parameters.

Methods

A prospective, multicenter, pharmacogenetic pilot study was performed in the context of two separate oral imatinib bioequivalence clinical trials, which included 26 healthy volunteers. DNA was extracted in order to analyze polymorphisms in genes CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and ABCB1. Imatinib plasma concentrations were measured by HPLC–MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods using WinNonlin software.

Results

Volunteers (n = 26; aged 24 ± 3 years; 69% male) presented regular pharmacokinetic imatinib data (concentration at 24 h, 436 ± 140 ng/mL and at 72 h, 40 ± 26 ng/mL; AUC0–72 32,868 ± 10,713 ng/mL⋅h; and Cmax 2074 ± 604 ng/mL). CYP2B6 516GT carriers showed a significant reduction of imatinib concentration at 24 h (23%, 391 ng/dL vs 511 ng/dL in 516GG carriers, p = 0.005) and elimination half-life (11%, 12.6 h vs 14.1 h in 516GG carriers, p = 0.041). Carriers for CYP3A4 (*22/*22, *1/*20 and *1/*22 variants) showed a reduced frequency of adverse events compared to *1/*1 carriers (0 vs 64%, p = 0.033). The other polymorphisms analyzed did not influence pharmacokinetics or drug toxicity.

Conclusion

CYP2B6 G516T and CYP3A4 *20,*22 polymorphisms could influence imatinib plasma concentrations and safety profile, after single-dose administration to healthy subjects. This finding needs to be confirmed before it is implemented in clinical practice in oncological patients under treatment with imatinib.

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References

  1. Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109(8):3496–9. https://doi.org/10.1182/blood-2006-07-036012.

    Article  CAS  PubMed  Google Scholar 

  2. Takahashi N, Wakita H, Miura M, Scott SA, Nishii K, Masuko M, et al. Correlation between imatinib pharmacokinetics and clinical response in Japanese patients with chronic-phase chronic myeloid leukemia. Clin Pharmacol Ther. 2010;88(6):809–13. https://doi.org/10.1038/clpt.2010.186.

    Article  CAS  PubMed  Google Scholar 

  3. Sohn SK, Oh SJ, Kim BS, Ryoo HM, Chung JS, Joo YD, et al. Trough plasma imatinib levels are correlated with optimal cytogenetic responses at 6 months after treatment with standard dose of imatinib in newly diagnosed chronic myeloid leukemia. Leukemia Lymphoma. 2011;52(6):1024–9. https://doi.org/10.3109/10428194.2011.563885.

    Article  CAS  PubMed  Google Scholar 

  4. Bouchet S, Titier K, Moore N, Lassalle R, Ambrosino B, Poulette S, et al. Therapeutic drug monitoring of imatinib in chronic myeloid leukemia: experience from 1216 patients at a centralized laboratory. Fundam Clin Pharmacol. 2013;27(6):690–7. https://doi.org/10.1111/fcp.12007.

    Article  CAS  PubMed  Google Scholar 

  5. Mahon FX. Pharmacologic monitoring and determinants of intracytoplasmic drug levels. Best Pract Res Clin Haematol. 2009;22(3):381–6. https://doi.org/10.1016/j.beha.2009.09.007.

    Article  PubMed  Google Scholar 

  6. Evans WE, McLeod HL. Pharmacogenomics-drug disposition, drug targets, and side effects. N Engl J Med. 2003;348(6):538–49. https://doi.org/10.1056/NEJMra020526.

    Article  CAS  PubMed  Google Scholar 

  7. Singh O, Chan JY, Lin K, Heng CC, Chowbay B. SLC22A1-ABCB1 haplotype profiles predict imatinib pharmacokinetics in Asian patients with chronic myeloid leukemia. PLoS One. 2012;7(12):e51771. https://doi.org/10.1371/journal.pone.0051771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Angelini S, Soverini S, Ravegnini G, Barnett M, Turrini E, Thornquist M, et al. Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy. Haematologica. 2013;98(2):193–200. https://doi.org/10.3324/haematol.2012.066480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Delord M, Rousselot P, Cayuela JM, Sigaux F, Guilhot J, Preudhomme C, et al. High imatinib dose overcomes insufficient response associated with ABCG2 haplotype in chronic myelogenous leukemia patients. Oncotarget. 2013;4(10):1582–91. https://doi.org/10.18632/oncotarget.1050.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Noguchi K, Katayama K, Sugimoto Y. Human ABC transporter ABCG2/BCRP expression in chemoresistance: basic and clinical perspectives for molecular cancer therapeutics. Pharmgenom Pers Med. 2014;7:53–64. https://doi.org/10.2147/pgpm.s38295.

    Article  Google Scholar 

  11. Dressman MA, Malinowski R, McLean LA, Gathmann I, Capdeville R, Hensley M, et al. Correlation of major cytogenetic response with a pharmacogenetic marker in chronic myeloid leukemia patients treated with imatinib (STI571). Clin Cancer Res. 2004;10(7):2265–71.

    Article  CAS  Google Scholar 

  12. Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K, et al. Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia. Clin Cancer Res. 2009;15(14):4750–8. https://doi.org/10.1158/1078-0432.ccr-09-0145.

    Article  CAS  PubMed  Google Scholar 

  13. Quiñones SL, Rosero PM, Roco AÁ, Moreno TI, Sasso AJ, Varela FN, et al. Papel de las enzimas citocromo p450 en el metabolismo de fármacos antineoplásicos: Situación actual y perspectivas terapéuticas. Revista médica de Chile. 2008;136:1327–35.

    Article  Google Scholar 

  14. Nelson DR. The cytochrome p450 homepage. Hum Genom. 2009;4(1):59–655.

    Article  CAS  Google Scholar 

  15. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76(3):391–6.

    PubMed  Google Scholar 

  16. Maddin N, Husin A, Gan SH, Aziz BA, Ankathil R. Impact of CYP3A4*18 and CYP3A5*3 Polymorphisms on Imatinib Mesylate Response Among Chronic Myeloid Leukemia Patients in Malaysia. Oncol Ther. 2016;4(2):303–14. https://doi.org/10.1007/s40487-016-0035-x.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Gardner ER, Burger H, van Schaik RH, van Oosterom AT, de Bruijn EA, Guetens G, et al. Association of enzyme and transporter genotypes with the pharmacokinetics of imatinib. Clin Pharmacol Ther. 2006;80(2):192–201. https://doi.org/10.1016/j.clpt.2006.05.003.

    Article  CAS  PubMed  Google Scholar 

  18. Kassogue Y, Quachouh M, Dehbi H, Quessar A, Benchekroun S, Nadifi S. Functional polymorphism of CYP2B6 G15631T is associated with hematologic and cytogenetic response in chronic myeloid leukemia patients treated with imatinib. Med Oncol (Northwood, London, England). 2014;31(1):782. https://doi.org/10.1007/s12032-013-0782-6.

    Article  CAS  Google Scholar 

  19. Salimizand H, Amini S, Abdi M, Ghaderi B, Azadi NA. Concurrent effects of ABCB1 C3435T, ABCG2 C421A, and XRCC1 Arg194Trp genetic polymorphisms with risk of cancer, clinical output, and response to treatment with imatinib mesylate in patients with chronic myeloid leukemia. Tumour Biol J Int Soc Oncodev Biol Med. 2016;37(1):791–8. https://doi.org/10.1007/s13277-015-3874-4.

    Article  CAS  Google Scholar 

  20. Guideline on the investigation of bioequivalence. Committee for Medicinal Products for Human Use. European Medicines Agency; 2010.

  21. Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharmacol Ther. 1977;21(3):247–54. https://doi.org/10.1002/cpt1977213247.

    Article  CAS  PubMed  Google Scholar 

  22. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008;83(2):234–42. https://doi.org/10.1038/sj.clpt.6100406.

    Article  CAS  PubMed  Google Scholar 

  23. Caudle KE, Dunnenberger HM, Freimuth RR, Peterson JF, Burlison JD, Whirl-Carrillo M, et al. Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet Med Off J Am Coll Med Genet. 2017;19(2):215–23. https://doi.org/10.1038/gim.2016.87.

    Article  Google Scholar 

  24. Apellaniz-Ruiz M, Inglada-Perez L, Naranjo ME, Sanchez L, Mancikova V, Curras-Freixes M, et al. High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme. Pharmacogenom J. 2015;15(3):288–92. https://doi.org/10.1038/tpj.2014.67.

    Article  CAS  Google Scholar 

  25. Leveque D, Maloisel F. Clinical pharmacokinetics of imatinib mesylate. In Vivo (Athens, Greece). 2005;19(1):77–84.

    CAS  Google Scholar 

  26. Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin Pharmacokinet. 2005;44(9):879–94. https://doi.org/10.2165/00003088-200544090-00001.

    Article  CAS  PubMed  Google Scholar 

  27. Gotta V, Buclin T, Csajka C, Widmer N. Systematic review of population pharmacokinetic analyses of imatinib and relationships with treatment outcomes. Ther Drug Monit. 2013;35(2):150–67. https://doi.org/10.1097/FTD.0b013e318284ef11.

    Article  CAS  PubMed  Google Scholar 

  28. Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J, Rahman A, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res Off J Am Assoc Cancer Res. 2002;8(5):935–42.

    CAS  Google Scholar 

  29. van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009;35(8):692–706. https://doi.org/10.1016/j.ctrv.2009.08.004.

    Article  CAS  PubMed  Google Scholar 

  30. Petain A, Kattygnarath D, Azard J, Chatelut E, Delbaldo C, Geoerger B, et al. Population pharmacokinetics and pharmacogenetics of imatinib in children and adults. Clin Cancer Res. 2008;14(21):7102–9. https://doi.org/10.1158/1078-0432.ccr-08-0950.

    Article  CAS  PubMed  Google Scholar 

  31. Liu J, Chen Z, Chen H, Hou Y, Lu W, He J, et al. Genetic polymorphisms contribute to the individual variations of imatinib mesylate plasma levels and adverse reactions in Chinese GIST patients. Int J Mol Sci. 2017;18(3):603. https://doi.org/10.3390/ijms18030603.

    Article  CAS  PubMed Central  Google Scholar 

  32. Foti RS, Rock DA, Wienkers LC, Wahlstrom JL. Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab Dispos Biol Fate Chem. 2010;38(6):981–7. https://doi.org/10.1124/dmd.110.032094.

    Article  CAS  PubMed  Google Scholar 

  33. Emoto C, Murayama N, Rostami-Hodjegan A, Yamazaki H. Methodologies for investigating drug metabolism at the early drug discovery stage: prediction of hepatic drug clearance and P450 contribution. Curr Drug Metab. 2010;11(8):678–85. https://doi.org/10.2174/138920010794233503.

    Article  CAS  PubMed  Google Scholar 

  34. Adeagbo BA, Bolaji OO, Olugbade TA, Durosinmi MA, Bolarinwa RA, Masimirembwa C. Influence of CYP3A5*3 and ABCB1 C3435T on clinical outcomes and trough plasma concentrations of imatinib in Nigerians with chronic myeloid leukaemia. J Clin Pharm Ther. 2016;41(5):546–51. https://doi.org/10.1111/jcpt.12424.

    Article  CAS  PubMed  Google Scholar 

  35. Cerveny L, Svecova L, Anzenbacherova E, Vrzal R, Staud F, Dvorak Z, et al. Valproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane X receptor pathways. Drug Metab Dispos Biol Fate Chem. 2007;35(7):1032–41. https://doi.org/10.1124/dmd.106.014456.

    Article  CAS  PubMed  Google Scholar 

  36. Gurney H, Wong M, Balleine RL, Rivory LP, McLachlan AJ, Hoskins JM, et al. Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype. Clin Pharmacol Ther. 2007;82(1):33–40. https://doi.org/10.1038/sj.clpt.6100201.

    Article  CAS  PubMed  Google Scholar 

  37. Yamakawa Y, Hamada A, Nakashima R, Yuki M, Hirayama C, Kawaguchi T, et al. 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. 2011;33(2):244–50. https://doi.org/10.1097/FTD.0b013e31820beb02.

    Article  CAS  PubMed  Google Scholar 

  38. Dulucq S, Bouchet S, Turcq B, Lippert E, Etienne G, Reiffers J, et al. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2008;112(5):2024–7. https://doi.org/10.1182/blood-2008-03-147744.

    Article  CAS  PubMed  Google Scholar 

  39. Harivenkatesh N, Kumar L, Bakhshi S, Sharma A, Kabra M, Velpandian T, et al. 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. 2017;120:138–45. https://doi.org/10.1016/j.phrs.2017.03.011.

    Article  CAS  PubMed  Google Scholar 

  40. Dulucq S, Krajinovic M. The pharmacogenetics of imatinib. Genome Med. 2010;2(11):85. https://doi.org/10.1186/gm206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pryde DC, Dalvie D, Hu Q, Jones P, Obach RS, Tran TD. Aldehyde oxidase: an enzyme of emerging importance in drug discovery. J Med Chem. 2010;53(24):8441–600. https://doi.org/10.1021/jm100888d.

    Article  CAS  PubMed  Google Scholar 

  42. Abbasi A, Paragas EM, Joswig-Jones CA, Rodgers JT, Jones JP. The time-course of aldehyde oxidase and the reason why it is nonlinear. Drug Metab Dispos. 2019. https://doi.org/10.1124/dmd.118.085787.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Dick RA. Refinement of In vitro methods for identification of aldehyde oxidase substrates reveals metabolites of kinase inhibitors. Drug Metab Dispos Biol Fate Chem. 2018;46(6):846–59. https://doi.org/10.1124/dmd.118.080960.

    Article  CAS  PubMed  Google Scholar 

  44. Petain A, Kattygnarath D, Azard J, Chatelut E, Delbaldo C, Geoerger B, et al. Population pharmacokinetics and pharmacogenetics of imatinib in children and adults. Clin Cancer Res Off J Am Assoc Cancer Res. 2008;14(21):7102–9. https://doi.org/10.1158/1078-0432.ccr-08-0950.

    Article  CAS  Google Scholar 

  45. Liu J, Chen Z, Chen H, Hou Y, Lu W, He J, et al. Genetic Polymorphisms contribute to the individual variations of imatinib mesylate plasma levels and adverse reactions in Chinese GIST patients. Int J Mol Sci. 2017. https://doi.org/10.3390/ijms18030603.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank the help received from nursery of clinical trial units and the altruism and patience of patients included in the study.

Author information

Authors and Affiliations

  1. Alicante Clinical Trials Unit, Department of Health, Alicante-General Hospital, Alicante, Spain

    María Ángeles Pena & Ana M. Peiró

  2. Clinical Pharmacology Service, Department of Health, Alicante-General Hospital, c/Pintor Baeza, 12, 03010, Alicante, Spain

    María Ángeles Pena & Ana M. Peiró

  3. Alicante Institute for Health and Biomedical Research (ISABIAL Foundation), Alicante, Spain

    Javier Muriel

  4. Clinical Pharmacology Service, University Hospital La Princesa, Autonomous University of Madrid, Madrid, Spain

    Miriam Saiz-Rodríguez & Francisco Abad-Santos

  5. Clinical Pharmacology Department, La Paz University Hospital, Universidad Autónoma de Madrid. IdiPAZ, Madrid, Spain

    Alberto M. Borobia & Jesús Frías

  6. Institute Teófilo Hernando for Drug I+D, School of Medicine, Autonomous University of Madrid, Madrid, Spain

    Francisco Abad-Santos

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  1. María Ángeles Pena
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Contributions

MÁP conceived and planned the experiment, got the grant of FISABIO and took the lead in writing the manuscript and contributed to the interpretation of the results. Javier Muriel designed the model and the computational framework, analyzed the data, and gave support in writing the manuscript. MS-R carried out the experiments. AMB, FA-S, JF conceived and planned the experiments and contributed to the interpretation of the result. AMP took the lead in writing the manuscript and contributed to the interpretation of the result. All authors provided critical review and helped shape the research, analysis and manuscript.

Corresponding author

Correspondence to Ana M. Peiró.

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Funding

Present study was partially funded by Foundation for the Promotion of Health and Biomedical Research of the Valencian Community (FISABIO, Valencia, Spain; code: UGP-15-212).

Conflict of interest

All authors declare no conflict of interest.

Ethics approval

All procedures were performed at Clinical Research and Clinical Trials Unit (Hospital La Paz, Madrid, Spain) and Alicante Clinical Trials Unit (Department of Health Alicante-General Hospital, Alicante, Spain). The study was approved by the local Ethics Committees and carried out in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent to participate

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

Availability of data and material (data transparency)

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability (software application or custom code)

All data and materials as well as software application or custom code support our published claims and comply with field standards.

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Pena, M.Á., Muriel, J., Saiz-Rodríguez, M. et al. Effect of Cytochrome P450 and ABCB1 Polymorphisms on Imatinib Pharmacokinetics After Single-Dose Administration to Healthy Subjects. Clin Drug Investig 40, 617–628 (2020). https://doi.org/10.1007/s40261-020-00921-7

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