Top

Published in:

01-08-2017 | Original Research Article

CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients

Authors: Daniel T. Barratt, Hannah K. Cox, Andrew Menelaou, David T. Yeung, Deborah L. White, Timothy P. Hughes, Andrew A. Somogyi

Published in: Clinical Pharmacokinetics | Issue 8/2017

Abstract

Objective

The aims of this study were to determine the effects of the CYP2C8*3 and *4 polymorphisms on imatinib metabolism and plasma imatinib concentrations in chronic myeloid leukaemia (CML) patients.

Methods

We genotyped 210 CML patients from the TIDELII trial receiving imatinib 400–800 mg/day for CYP2C8*3 (rs11572080, rs10509681) and *4 (rs1058930). Steady-state trough total plasma N-desmethyl imatinib (major metabolite):imatinib concentration ratios (metabolic ratios) and trough total plasma imatinib concentrations were compared between genotypes (one-way ANOVA with Tukey post hoc).

Results

CYP2C8*3 (n = 34) and *4 (n = 15) carriers had significantly higher (P < 0.01) and lower (P < 0.01) metabolic ratios, respectively, than CYP2C8*1/*1 (n = 147) patients (median ± standard deviation: 0.28 ± 0.08, 0.18 ± 0.06 and 0.22 ± 0.08, respectively). Plasma imatinib concentrations were consequently > 50% higher for CYP2C8*1/*4 than for CYP2C8*1/*1 and CYP2C8*3 carriers (2.18 ± 0.66 vs. 1.45 ± 0.74 [P < 0.05] and 1.36 ± 0.98 μg/mL [P < 0.05], respectively).

Conclusions

CYP2C8 genotype significantly alters imatinib metabolism in patients through gain- and loss-of-function mechanisms.

Available only for authorised users

Maino E, Sancetta R, Viero P, Imbergamo S, Scattolin AM, Vespignani M, et al. Current and future management of Ph/BCR-ABL positive ALL. Expert Rev Anticancer Ther. 2014;14(6):723–40. doi:10.1586/14737140.2014.895669.CrossRefPubMed

Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management. Am J Hematol. 2014;89(5):547–56. doi:10.1002/ajh.23691.CrossRefPubMed

Linch M, Claus J, Benson C. Update on imatinib for gastrointestinal stromal tumors: duration of treatment. Onco Targets Ther. 2013;6:1011–23. doi:10.2147/ott.s31260.PubMedPubMedCentral

Gleevec NDA 021588 label information. Revised Sep 2016. US Food and Drug Administration, Center for Drug Evaluation and Research; 2016. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021588s047lbl.pdf. Accessed 13 Oct 2016.

Gotta V, Bouchet S, Widmer N, Schuld P, Decosterd LA, Buclin T, et al. Large-scale imatinib dose-concentration-effect study in CML patients under routine care conditions. Leuk Res. 2014;38(7):764–72. doi:10.1016/j.leukres.2014.03.023.CrossRefPubMed

Widmer N, Bardin C, Chatelut E, Paci A, Beijnen J, Leveque D, et al. Review of therapeutic drug monitoring of anticancer drugs part two-targeted therapies. Eur J Cancer. 2014;50(12):2020–36. doi:10.1016/j.ejca.2014.04.015.CrossRefPubMed

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. doi:10.1182/blood-2006-07-036012.CrossRefPubMed

Larson RA, Druker BJ, Guilhot F, O’Brien SG, Riviere GJ, Krahnke T, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia. Blood. 2008;111(8):4022–8. doi:10.1182/blood-2007-10-116475.CrossRefPubMed

Berglund E, Ubhayasekera SJ, Karlsson F, Akcakaya P, Aluthgedara W, Ahlen J, et al. Intracellular concentration of the tyrosine kinase inhibitor imatinib in gastrointestinal stromal tumor cells. Anticancer Drugs. 2014;25(4):415–22. doi:10.1097/cad.0000000000000069.CrossRefPubMed

10.

Mlejnek P, Dolezel P, Faber E, Kosztyu P. Interactions of N-desmethyl imatinib, an active metabolite of imatinib, with P-glycoprotein in human leukemia cells. Ann Hematol. 2011;90(7):837–42. doi:10.1007/s00277-010-1142-7.CrossRefPubMed

11.

Manley PW, Blasco F, Mestan J, Aichholz R. The kinetic deuterium isotope effect as applied to metabolic deactivation of imatinib to the des-methyl metabolite, CGP74588. Bioorg Med Chem. 2013;21(11):3231–9. doi:10.1016/j.bmc.2013.03.038.CrossRefPubMed

12.

Skoglund K, Boiso Moreno S, Jonsson JI, Vikingsson S, Carlsson B, Green H. Single-nucleotide polymorphisms of ABCG2 increase the efficacy of tyrosine kinase inhibitors in the K562 chronic myeloid leukemia cell line. Pharmacogenet Genomics. 2014;24(1):52–61. doi:10.1097/FPC.0000000000000022.CrossRefPubMed

13.

Skoglund K, Moreno SB, Baytar M, Jonsson JI, Green H. ABCB1 haplotypes do not influence transport or efficacy of tyrosine kinase inhibitors in vitro. Pharmgenomics Pers Med. 2013;6:63–72. doi:10.2147/PGPM.S45522.PubMedPubMedCentral

14.

Josephs DH, Fisher DS, Spicer J, Flanagan RJ. Clinical pharmacokinetics of tyrosine kinase inhibitors: implications for therapeutic drug monitoring. Ther Drug Monit. 2013;35(5):562–87. doi:10.1097/FTD.0b013e318292b931.PubMed

15.

Gschwind HP, Pfaar U, Waldmeier F, Zollinger M, Sayer C, Zbinden P, et al. Metabolism and disposition of imatinib mesylate in healthy volunteers. Drug Metab Dispos. 2005;33(10):1503–12. doi:10.1124/dmd.105.004283.CrossRefPubMed

16.

Di Gion P, Kanefendt F, Lindauer A, Scheffler M, Doroshyenko O, Fuhr U, et al. Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on pyrimidines, pyridines and pyrroles. Clin Pharmacokinet. 2011;50(9):551–603. doi:10.2165/11593320-000000000-00000.CrossRefPubMed

17.

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. doi:10.1111/fcp.12007.CrossRefPubMed

18.

de Wit D, Guchelaar HJ, den Hartigh J, Gelderblom H, van Erp NP. Individualized dosing of tyrosine kinase inhibitors: are we there yet? Drug Discov Today. 2015;20(1):18–36. doi:10.1016/j.drudis.2014.09.007.CrossRefPubMed

19.

Filppula AM, Laitila J, Neuvonen PJ, Backman JT. Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates. Br J Pharmacol. 2012;165(8):2787–98. doi:10.1111/j.1476-5381.2011.01732.x.CrossRefPubMedPubMedCentral

20.

Filppula AM, Neuvonen M, Laitila J, Neuvonen PJ, Backman JT. Autoinhibition of CYP3A4 leads to important role of CYP2C8 in imatinib metabolism. Drug Metab Dispos. 2013;41(1):50–9. doi:10.1124/dmd.112.048017.CrossRefPubMed

21.

Nebot N, Crettol S, d’Esposito F, Tattam B, Hibbs DE, Murray M. Participation of CYP2C8 and CYP3A4 in the N-demethylation of imatinib in human hepatic microsomes. Br J Pharmacol. 2010;161(5):1059–69. doi:10.1111/j.1476-5381.2010.00946.x.CrossRefPubMedPubMedCentral

22.

Skoglund K, Richter J, Olsson-Stromberg U, Bergquist J, Aluthgedara W, Ubhayasekera SJ, et al. In vivo cytochrome P450 3A isoenzyme activity and pharmacokinetics of imatinib in relation to therapeutic outcome in patients with chronic myeloid leukemia. Ther Drug Monit. 2016;38(2):230–8. doi:10.1097/FTD.0000000000000268.CrossRefPubMed

23.

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. doi:10.1038/sj.clpt.6100201.CrossRefPubMed

24.

Widmer N, Decosterd LA, Csajka C, Leyvraz S, Duchosal MA, Rosselet A, et al. Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein [published erratum appears in Br J Clin Pharmacol 2010; 70 (2):316]. Br J Clin Pharmacol. 2006;62(1):97–112. doi:10.1111/j.1365-2125.2006.02719.x.CrossRefPubMedPubMedCentral

25.

Schmidli H, Peng B, Riviere GJ, Capdeville R, Hensley M, Gathmann I, et al. Population pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia: results of a phase III study. Br J Clin Pharmacol. 2005;60(1):35–44. doi:10.1111/j.1365-2125.2005.02372.x.CrossRefPubMedPubMedCentral

26.

van Erp NP, Gelderblom H, Karlsson MO, Li J, Zhao M, Ouwerkerk J, et al. Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. Clin Cancer Res. 2007;13(24):7394–400. doi:10.1158/1078-0432.CCR-07-0346.CrossRefPubMed

27.

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. doi:10.1371/journal.pone.0051771.CrossRefPubMedPubMedCentral

28.

Seong SJ, Lim M, Sohn SK, Moon JH, Oh SJ, Kim BS, et al. Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients. Ann Oncol. 2013;24(3):756–60. doi:10.1093/annonc/mds532.CrossRefPubMed

29.

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. doi:10.1097/FTD.0b013e31820beb02.PubMed

30.

Takahashi N, Miura M, Scott SA, Kagaya H, Kameoka Y, Tagawa H, et al. 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. 2010;55(11):731–7. doi:10.1038/jhg.2010.98.CrossRefPubMed

31.

Khan MS, Barratt DT, Somogyi AA. Impact of CYP2C8*3 polymorphism on in vitro metabolism of imatinib to N-desmethyl imatinib. Xenobiotica. 2015:1–10. doi: 10.3109/00498254.2015.1060649.

32.

Bahadur N, Leathart JB, Mutch E, Steimel-Crespi D, Dunn SA, Gilissen R, et al. CYP2C8 polymorphisms in Caucasians and their relationship with paclitaxel 6alpha-hydroxylase activity in human liver microsomes. Biochem Pharmacol. 2002;64(11):1579–89.CrossRefPubMed

33.

Gao Y, Liu D, Wang H, Zhu J, Chen C. Functional characterization of five CYP2C8 variants and prediction of CYP2C8 genotype-dependent effects on in vitro and in vivo drug-drug interactions. Xenobiotica. 2010;40(7):467–75. doi:10.3109/00498254.2010.487163.CrossRefPubMed

34.

Jiang H, Zhong F, Sun L, Feng W, Huang ZX, Tan X. Structural and functional insights into polymorphic enzymes of cytochrome P450 2C8. Amino Acids. 2011;40(4):1195–204. doi:10.1007/s00726-010-0743-8.CrossRefPubMed

35.

Wang Z, Wang S, Huang M, Hu H, Yu L, Zeng S. Characterizing the effect of cytochrome P450 (CYP) 2C8, CYP2C9, and CYP2D6 genetic polymorphisms on stereoselective N-demethylation of fluoxetine. Chirality. 2014;26(3):166–73. doi:10.1002/chir.22289.CrossRefPubMed

36.

Rochat B, Zoete V, Grosdidier A, von Grunigen S, Marull M, Michielin O. In vitro biotransformation of imatinib by the tumor expressed CYP1A1 and CYP1B1. Biopharm Drug Dispos. 2008;29(2):103–18. doi:10.1002/bdd.598.CrossRefPubMed

37.

Yeung DT, Osborn MP, White DL, Branford S, Braley J, Herschtal A, et al. TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood. 2015;125(6):915–23. doi:10.1182/blood-2014-07-590315.CrossRefPubMedPubMedCentral

38.

R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2013.

39.

Fox J, Weisberg S. An R companion to applied regression. 2nd ed. Thousand Oaks: Sage; 2011.

40.

Hothorn T, Bretz F, Westfall P. Simultaneous inference in general parametric models. Biom J. 2008;50(3):346–63.CrossRefPubMed

41.

Bates D, Maechler M, Bolker B, Wlaker S. lme4: linear mixed-effects models using Eigen and S4. R package version 1.0-5. 2013. http://CRAN.R-project.org/package=lme4. Accessed 19 Apr 2016.

42.

Fox J. Effect displays in R for generalised linear models. J Stat Softw. 2003;8(15):1–27.CrossRef

43.

Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994;270(1):414–23.PubMed

44.

Di Paolo A, Polillo M, Capecchi M, Cervetti G, Barate C, Angelini S, et al. The c.480C > G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia. Pharmacogenomics J. 2014;14(4):328–35. doi:10.1038/tpj.2014.7.CrossRefPubMed

45.

Gandia P, Arellano C, Lafont T, Huguet F, Malard L, Chatelut E. Should therapeutic drug monitoring of the unbound fraction of imatinib and its main active metabolite N-desmethyl-imatinib be developed? Cancer Chemother Pharmacol. 2013;71:531–6. doi:10.1007/s00280-012-2035-3.CrossRefPubMed

46.

Gater A, Heron L, Abetz-Webb L, Coombs J, Simmons J, Guilhot F, et al. Adherence to oral tyrosine kinase inhibitor therapies in chronic myeloid leukemia. Leuk Res. 2012;36(7):817–25. doi:10.1016/j.leukres.2012.01.021.CrossRefPubMed

47.

Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422):56–65. doi:10.1038/nature11632.CrossRefPubMed

48.

Stingl Kirchheiner JC, Brockmoller J. Why, when, and how should pharmacogenetics be applied in clinical studies? Current and future approaches to study designs. Clin Pharmacol Ther. 2011;89(2):198–209. doi:10.1038/clpt.2010.274.CrossRefPubMed

49.

Ritchie MD. The success of pharmacogenomics in moving genetic association studies from bench to bedside: study design and implementation of precision medicine in the post-GWAS era. Hum Genet. 2012;131(10):1615–26. doi:10.1007/s00439-012-1221-z.CrossRefPubMedPubMedCentral

Title: CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients
Authors: Daniel T. Barratt
Hannah K. Cox
Andrew Menelaou
David T. Yeung
Deborah L. White
Timothy P. Hughes
Andrew A. Somogyi
Publication date: 01-08-2017
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 8/2017
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-016-0494-0

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients

Abstract

Objective

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Objective

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 8/2017

Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine

A New CYP3A5*3 and CYP3A4*22 Cluster Influencing Tacrolimus Target Concentrations: A Population Approach

Pharmacokinetics of Daratumumab Following Intravenous Infusion in Relapsed or Refractory Multiple Myeloma After Prior Proteasome Inhibitor and Immunomodulatory Drug Treatment

Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus

Renal Drug Transporters and Drug Interactions

Pharmacokinetics and Pharmacodynamics of Afamelanotide and its Clinical Use in Treating Dermatologic Disorders

A New CYP3A53 and CYP3A422 Cluster Influencing Tacrolimus Target Concentrations: A Population Approach