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Role of genetic variation in docetaxel-induced neutropenia and pharmacokinetics

The Pharmacogenomics Journal volume 16, pages 519–524 (2016)Cite this article

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Abstract

Docetaxel is used for treatment of several solid malignancies. In this study, we aimed for predicting docetaxel clearance and docetaxel-induced neutropenia by developing several genetic models. Therefore, pharmacokinetic data and absolute neutrophil counts (ANCs) of 213 docetaxel-treated cancer patients were collected. Next, patients were genotyped for 1936 single nucleotide polymorphisms (SNPs) in 225 genes using the drug-metabolizing enzymes and transporters platform and thereafter split into two cohorts. The combination of SNPs that best predicted severe neutropenia or low clearance was selected in one cohort and validated in the other. Patients with severe neutropenia had lower docetaxel clearance than patients with ANCs in the normal range (P=0.01). Severe neutropenia was predicted with 70% sensitivity. True low clearance (1 s.d.<mean clearance) was identified in 80% of cases. These models however did not reach statistical significance. To improve the predictive value of these models, the addition of non-genetic influencing factors is needed.

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References

  1. Mosteller RD . Simplified calculation of body-surface area. N Engl J Med 1987; 317: 1098.

    CAS  PubMed  Google Scholar 

  2. Bins S, Ratain MJ, Mathijssen RH . Conventional dosing of anticancer agents: precisely wrong or just inaccurate? Clin Pharmacol Ther 2014; 95: 361–364.

    Article  CAS  Google Scholar 

  3. Baker SD, Li J, ten Tije AJ, Figg WD, Graveland W, Verweij J et al. Relationship of systemic exposure to unbound docetaxel and neutropenia. Clin Pharmacol Ther 2005; 77: 43–53.

    Article  CAS  Google Scholar 

  4. de Graan AJ, Loos WJ, Friberg LE, Baker SD, van der Bol JM, van Doorn L et al. Influence of smoking on the pharmacokinetics and toxicity profiles of taxane therapy. Clin Cancer Res 2012; 18: 4425–4432.

    Article  CAS  Google Scholar 

  5. Wonganan P, Zamboni WC, Strychor S, Dekker JD, Croyle MA . Drug-virus interaction: effect of administration of recombinant adenoviruses on the pharmacokinetics of docetaxel in a rat model. Cancer Gene Ther 2009; 16: 405–414.

    Article  CAS  Google Scholar 

  6. Puisset F, Alexandre J, Treluyer JM, Raoul V, Roche H, Goldwasser F et al. Clinical pharmacodynamic factors in docetaxel toxicity. Br J Cancer 2007; 97: 290–296.

    Article  CAS  Google Scholar 

  7. Bruno R, Vivier N, Veyrat-Follet C, Montay G, Rhodes GR . Population pharmacokinetics and pharmacokinetic-pharmacodynamic relationships for docetaxel. Invest New Drugs 2001; 19: 163–169.

    Article  CAS  Google Scholar 

  8. Chew SC, Sandanaraj E, Singh O, Chen X, Tan EH, Lim WT et al. Influence of SLCO1B3 haplotype-tag SNPs on docetaxel disposition in Chinese nasopharyngeal cancer patients. Br J Clin Pharmacol 2012; 73: 606–618.

    Article  CAS  Google Scholar 

  9. Baker SD, Verweij J, Cusatis GA, van Schaik RH, Marsh S, Orwick SJ et al. Pharmacogenetic pathway analysis of docetaxel elimination. Clin Pharmacol Ther 2009; 85: 155–163.

    Article  CAS  Google Scholar 

  10. Mathijssen RH, Sparreboom A, Verweij J . Determining the optimal dose in the development of anticancer agents. Nat Rev Clin Oncol 2014; 11: 272–281.

    Article  CAS  Google Scholar 

  11. Kraut EH, Rhoades C, Zhang Y, Cheng H, Aimiumu J, Chen P et al. Phase I and pharmacokinetic study of erlotinib (OSI-774) in combination with docetaxel in squamous cell carcinoma of the head and neck (SSCHN). Cancer Chemother Pharmacol 2011; 67: 579–586.

    Article  CAS  Google Scholar 

  12. Moulder S, Gladish G, Ensor J, Gonzalez-Angulo AM, Cristofanilli M, Murray JL et al. A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer. Cancer 2012; 118: 2378–2384.

    Article  CAS  Google Scholar 

  13. Itoh K, Sasaki Y, Fujii H, Minami H, Ohtsu T, Wakita H et al. Study of dose escalation and sequence switching of administration of the combination of docetaxel and doxorubicin in advanced breast cancer. Clin Cancer Res 2000; 6: 4082–4090.

    CAS  PubMed  Google Scholar 

  14. Hamberg P, Mathijssen RH, de Bruijn P, Leonowens C, van der Biessen D, Eskens FA et al. Impact of pazopanib on docetaxel exposure: results of a phase I combination study with two different docetaxel schedules. Cancer Chemother Pharmacol 2014; 75: 365–371.

    Article  Google Scholar 

  15. Krens SD, McLeod HL, Hertz DL . Pharmacogenetics, enzyme probes and therapeutic drug monitoring as potential tools for individualizing taxane therapy. Pharmacogenomics 2013; 14: 555–574.

    Article  CAS  Google Scholar 

  16. SPC_docetaxel. Taxotere 160mg/8ml concentrate for solution for infusion. Available at: http://www.medicines.org.uk/emc/medicine/25464/spc.

  17. de Graan AJ, Elens L, Smid M, Martens JW, Sparreboom A, Nieuweboer AJ et al. A pharmacogenetic predictive model for paclitaxel clearance based on the DMET platform. Clin Cancer Res 2013; 19: 5210–5217.

    Article  CAS  Google Scholar 

  18. Lustig V, Rosing H, Warmerdam LJC, Huizing MT, Bokkel Huinink WW, Dubbelman AC et al. Limited sampling models for the pharmacokinetics of docetaxel. Clin Drug Investig 1997; 13: 247–254.

    Article  CAS  Google Scholar 

  19. de Graan AJ, Lancaster CS, Obaidat A, Hagenbuch B, Elens L, Friberg LE et al. Influence of polymorphic OATP1B-type carriers on the disposition of docetaxel. Clin Cancer Res 2012; 18: 4433–4440.

    Article  CAS  Google Scholar 

  20. Dumaual C, Miao X, Daly TM, Bruckner C, Njau R, Fu DJ et al. Comprehensive assessment of metabolic enzyme and transporter genes using the Affymetrix Targeted Genotyping System. Pharmacogenomics 2007; 8: 293–305.

    Article  CAS  Google Scholar 

  21. Cuzick J . A Wilcoxon-type test for trend. Stat Med 1985; 4: 87–90.

    Article  CAS  Google Scholar 

  22. Nieuweboer AJ, de Morrée ES, de Graan AJ, Sparreboom A, de Wit R, Mathijssen RH . Inter-patient variability in docetaxel pharmacokinetics: a review. Cancer Treat Rev 2015; 41: 605–613.

    Article  CAS  Google Scholar 

  23. Franke RM, Carducci MA, Rudek MA, Baker SD, Sparreboom A . Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer. J Clin Oncol 2010; 28: 4562–4567.

    Article  CAS  Google Scholar 

  24. Fajac A, Gligorov J, Rezai K, Levy P, Levy E, Selle F et al. Effect of ABCB1 C3435T polymorphism on docetaxel pharmacokinetics according to menopausal status in breast cancer patients. Br J Cancer 2010; 103: 560–566.

    Article  CAS  Google Scholar 

  25. Iusuf D, Hendrikx JJ, van Esch A, van de Steeg E, Wagenaar E, Rosing H et al. Human OATP1B1, OATP1B3 and OATP1A2 can mediate the in vivo uptake and clearance of docetaxel. Int J Cancer 2015; 136: 225–233.

    Article  CAS  Google Scholar 

  26. Ihunnah CA, Wada T, Philips BJ, Ravuri SK, Gibbs RB, Kirisci L et al. Estrogen sulfotransferase/SULT1E1 promotes human adipogenesis. Mol Cell Biol 2014; 34: 1682–1694.

    Article  Google Scholar 

  27. de Graan AJ, Elens L, Sprowl JA, Sparreboom A, Friberg LE, van der Holt B et al. CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity. Clin Cancer Res 2013; 19: 3316–3324.

    Article  CAS  Google Scholar 

  28. Argyriou AA, Kyritsis AP, Makatsoris T, Kalofonos HP . Chemotherapy-induced peripheral neuropathy in adults: a comprehensive update of the literature. Cancer Manag Res 2014; 6: 135–147.

    Article  Google Scholar 

  29. Lee JJ, Swain SM . Peripheral neuropathy induced by microtubule-stabilizing agents. J Clin Oncol 2006; 24: 1633–1642.

    Article  CAS  Google Scholar 

  30. Awada Z, Haider S, Tfayli A, Bazarbachi A, El-Saghir NS, Salem Z et al. Pharmacogenomics variation in drug metabolizing enzymes and transporters in relation to docetaxel toxicity in Lebanese breast cancer patients: paving the way for OMICs in low and middle income countries. OMICS 2013; 17: 353–367.

    Article  CAS  Google Scholar 

  31. Liu S, Stoesz SP, Pickett CB . Identification of a novel human glutathione S-transferase using bioinformatics. Arch Biochem Biophys 1998; 352: 306–313.

    Article  CAS  Google Scholar 

  32. Edvardsen H, Brunsvig PF, Solvang H, Tsalenko A, Andersen A, Syvanen AC et al. SNPs in genes coding for ROS metabolism and signalling in association with docetaxel clearance. Pharmacogenomics J 2010; 10: 513–523.

    Article  CAS  Google Scholar 

  33. Li H, Wang X, Wang X . The impact of CDA A79C gene polymorphisms on the response and hematologic toxicity in gemcitabine-treated patients: A meta-analysis. Int J Biol Markers 2014; 29: e224–e232.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank all patients for their participation in this study. Also, we would like to thank Lena E Friberg from the department of pharmaceutical biosciences, from the Uppsala University in Uppsala, Sweden for the NONMEM-modeling of the pharmacokinetic data. This work was supported by a scientific grant of the Dutch Cancer Society (EMCR 2010-4664).

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Authors and Affiliations

  1. Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands

    A J M Nieuweboer, M Smid, A-J M de Graan, P de Bruijn, F A L M Eskens, J W M Martens, R de Wit & R H J Mathijssen

  2. Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands

    S Elbouazzaoui & R H N van Schaik

  3. Department of Internal Medicine, St. Franciscus Gasthuis, Rotterdam, The Netherlands

    P Hamberg

  4. Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA

    A Sparreboom

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  1. A J M Nieuweboer
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Correspondence to R H N van Schaik.

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Nieuweboer, A., Smid, M., de Graan, AJ. et al. Role of genetic variation in docetaxel-induced neutropenia and pharmacokinetics. Pharmacogenomics J 16, 519–524 (2016). https://doi.org/10.1038/tpj.2015.66

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  • DOI: https://doi.org/10.1038/tpj.2015.66

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