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CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients

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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.

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Authors and Affiliations

  1. Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA, 5005, Australia

    Daniel T. Barratt, Hannah K. Cox & Andrew A. Somogyi

  2. Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia

    Daniel T. Barratt & Andrew A. Somogyi

  3. South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia

    Andrew Menelaou, David T. Yeung, Deborah L. White & Timothy P. Hughes

  4. Department of Haematology, SA Pathology, Adelaide, SA, Australia

    David T. Yeung & Timothy P. Hughes

  5. Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia

    David T. Yeung, Deborah L. White & Timothy P. Hughes

  6. Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, SA, Australia

    Andrew A. Somogyi

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  1. Daniel T. Barratt
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Correspondence to Daniel T. Barratt.

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Funding

This study was funded by the School of Medical Sciences (now Adelaide Medical School), University of Adelaide and a Royal Adelaide Hospital Research Foundation Clinical Project Grant.

Conflicts of Interest

DLW received research funding and honoraria from Novartis and BMS. TPH acted on the advisory board of, and received research funding and honoraria from, Novartis, BMS and Ariad. DTY received research funding and honoraria from, Novartis, BMS and Ariad. DTB, HKC, AM and AAS have no conflicts of interest to declare.

Ethical Approval

All procedures performed in studies involving human participants were 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.

Informed Consent

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

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Barratt, D.T., Cox, H.K., Menelaou, A. et al. CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients. Clin Pharmacokinet 56, 977–985 (2017). https://doi.org/10.1007/s40262-016-0494-0

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