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Research Article

Population pharmacokinetic and pharmacogenetics of imatinib in Chinese patients with chronic myeloid leukemia

    Qing Wang‡

    Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China

    Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, PR China

    ‡Authors contributed equally and are co-first authors

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    ,
    Zhi-Ping Jiang‡

    Laboratory of Clinical Pharmacology, Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China

    ‡Authors contributed equally and are co-first authors

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    ,
    Er-Qian Yu

    Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai 200040, PR China

    The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, PR China

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    ,
    Jing Zeng

    Department of Education & Research, Ningbo Medical Center, Li Huili Eastern Hospital, Ningbo, Zhejiang 315000, PR China

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    ,
    Yan Zhu

    Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China

    Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, PR China

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    ,
    Hua-Lin Cai

    Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China

    Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, PR China

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    ,
    Miao Yan

    Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China

    Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, PR China

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    ,
    Da-Xiong Xiang

    Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China

    Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, PR China

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    ,
    Xie-Lan Zhao

    Laboratory of Clinical Pharmacology, Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China

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    ,
    Ping Xu

    *Author for correspondence: Tel.: +86 731 85292074; Fax: +86 731 82258487;

    E-mail Address: xuping1109@csu.edu.cn

    Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China

    Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, PR China

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    ,
    Zheng Jiao

    **Author for correspondence:

    E-mail Address: zjiao@fudan.edu.cn

    Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai 200040, PR China

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    &
    Hoan Linh Banh

    Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China

    Institute of Clinical Pharmacy, Central South University, Changsha, Hunan 410011, PR China

    Faculty of Medicine & Dentistry/Department of Family Medicine, University of Alberta, 6-10 University Terrace, Edmonton, AB T6G 2T4, Canada

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    Published Online:15 Feb 2019https://doi.org/10.2217/pgs-2018-0139

    Abstract

    Aim: This study aimed to establish a population pharmacokinetic (PPK) model in Chinese patients with chronic myeloid leukemia, and to quantify the effects of pharmacogenetics on pharmacokinetic parameters of imatinib. Methods: A total of 229 plasma concentrations from 170 patients were analyzed. Nonlinear mixed effect model was used to establish the PPK model. Results: A one-compartment model with first-order absorption and first-order elimination adequately describes imatinib pharmacokinetics. Actual bodyweight shows slight effect on the estimated apparent clearance (CL/F) of imatinib in this study population. The final PPK model is: Ka (1/h) = 0.329; CL/F (l/h) = 9.25 × (actual bodyweight/70)0.228; V/F(l) = 222. Conclusion: Actual bodyweight has a slight effect on CL/F. Demographics, physiopathology and pharmacogenetics covariates have no significant effects on imatinib pharmacokinetics.

    References

    • 1 Druker BJ, Guilhot F, O'Brien SG et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 355(23), 2408–2417 (2006).
      Medline CASGoogle Scholar
    • 2 Jiang ZP, Zhao XL, Takahashi N et al. Trough concentration and ABCG2 polymorphism are better to predict imatinib response in chronic myeloid leukemia: a meta-analysis. Pharmacogenomics 18(1), 35–56 (2017).
      CASGoogle Scholar
    • 3 Miura M. Therapeutic drug monitoring of imatinib, nilotinib, and dasatinib for patients with chronic myeloid leukemia. Biol. Pharm. Bull. 38(5), 645–654 (2015).
      Medline CASGoogle Scholar
    • 4 Dulucq S, Krajinovic M. The pharmacogenetics of imanitib. Genome Med. 2(11), 85 (2010).
      Medline CASGoogle Scholar
    • 5 Larson RA, Druker BJ, Guilhot F et al. 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 (2008).
      Medline CASGoogle Scholar
    • 6 Takahashi N, Miura M, Scott SA 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. 55(11), 731–737 (2010).
      Medline CASGoogle Scholar
    • 7 Ahmed S, Zhou Z, Zhou J, Chen SQ. Pharmacogenomics of drug metabolizing enzymes and transporters: relevance to precision medicine. Genom. Proteom. Bioinform. 14(5), 298–313 (2016).
      MedlineGoogle Scholar
    • 8 Eechoute K, Sparreboom A, Burger H et al. Drug transporters and imatinib treatment: implications for clinical practice. Clin. Cancer Res. 17(3), 406–415 (2011).
      Medline CASGoogle Scholar
    • 9 Sprowl JA, Sparreboom A. Uptake carriers and oncology drug safety. Drug Metab. Dispos. 42(4), 611–622 (2014).
      MedlineGoogle Scholar
    • 10 Zhou F, Zhu L, Wang K, Murray M. Recent advance in the pharmacogenomics of human solute carrier transporters (SLCs) in drug disposition. Adv Drug Deliv Rev. 116, 21–36 (2017).
      Medline CASGoogle Scholar
    • 11 Ravegnini G, Sammarini G, Angelini S, Hrelia P. Pharmacogenetics of tyrosine kinase inhibitors in gastrointestinal stromal tumor and chronic myeloid leukemia. Expert Opin. Drug Metab. Toxicol. 12(7), 733–742 (2016).
      Medline CASGoogle Scholar
    • 12 Petain A, Kattygnarath D, Azard J et al. Population pharmacokinetics and pharmacogenetics of imatinib in children and adults. Clin. Cancer Res. 14(21), 7102–7109 (2008).
      Medline CASGoogle Scholar
    • 13 Yamakawa Y, Hamada A, Nakashima R 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. 33(2), 244–250 (2011).
      Medline CASGoogle Scholar
    • 14 Eechoute K, Fransson MN, Reyners AK et al. A long-term prospective population pharmacokinetic study on imatinib plasma concentrations in GIST patients. Clin. Cancer Res. 18(20), 5780–5787 (2012).
      Medline CASGoogle Scholar
    • 15 NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia version 1.2017 (2017). www.nccn.org/professionals/physician_gls/pdf/cml.pdf
      Google Scholar
    • 16 Baccarani M, Deininger MW, Rosti G et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122(6), 872–884 (2013).
      Medline CASGoogle Scholar
    • 17 Zeng J, Cai HL, Jiang ZP et al. A validated UPLC–MS/MS method for simultaneous determination of imatinib, dasatinib and nilotinib in human plasma. J. Pharmaceut. Analysis 7(6), 374–380 (2017).
      MedlineGoogle Scholar
    • 18 Delbaldo C, Chatelut E, Re M et al. Pharmacokinetic–pharmacodynamic relationships of imatinib and its main metabolite in patients with advanced gastrointestinal stromal tumors. Clin. Cancer Res. 12(20, Pt 1), 6073–6078 (2006).
      Medline CASGoogle Scholar
    • 19 Ding J, Wang Y, Lin W et al. A population pharmacokinetic model of valproic acid in pediatric patients with epilepsy: a non-linear pharmacokinetic model based on protein-binding saturation. Clin. Pharmacokinet. 54(3), 305–317 (2015).
      Medline CASGoogle Scholar
    • 20 Gotta V, Buclin T, Csajka C, Widmer N. Systematic review of population pharmacokinetic analyses of imatinib and relationships with treatment outcomes. Ther. Drug Monit. 35(2), 150–167 (2013).
      Medline CASGoogle Scholar
    • 21 Ansari M, Kalantary-Khandani B, Pardakhty A, Safavi M, Mosavi N, Mohajeri E. Population pharmacokinetics of imatinib and its application to the therapeutic drug monitoring: Middle East CML population. Gulf J. Oncolog. 1(22), 26–36 (2016).
      MedlineGoogle Scholar
    • 22 Golabchifar AA, Rezaee S, Ghavamzadeh A, Alimoghaddam K, Dinan NM, Rouini MR. Population pharmacokinetics of imatinib in Iranian patients with chronic-phase chronic myeloid leukemia. Cancer Chemother. Pharmacol. 74(1), 85–93 (2014).
      Medline CASGoogle Scholar
    • 23 Di Paolo A, Polillo M, Capecchi M et al. The c.480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia. Pharmacogenomics J. 14(4), 328–335 (2014).
      Medline CASGoogle Scholar
    • 24 Widmer N, Decosterd LA, Csajka C et al. Population pharmacokinetics of imatinib and the role of alpha-acid glycoprotein. Br. J. Clin. Pharmacol. 62(1), 97–112 (2006).
      Medline CASGoogle Scholar
    • 25 Adeagbo BA, Olugbade TA, Durosinmi MA, Bolarinwa RA, Ogungbenro K, Bolaji OO. Population pharmacokinetics of imatinib in Nigerians with chronic myeloid leukemia: clinical implications for dosing and resistance. J. Clin. Pharmacol. 57(12), 1554–1563 (2017).
      Medline CASGoogle Scholar
    • 26 Schmidli H, Peng B, Riviere GJ 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. 60(1), 35–44 (2005).
      Medline CASGoogle Scholar
    • 27 Menon-Andersen D, Mondick JT, Jayaraman B et al. Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults. Cancer Chemother. Pharmacol. 63(2), 229–238 (2009).
      Medline CASGoogle Scholar