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Proton pump inhibitors significantly increase the intracellular concentration of nilotinib, but not imatinib in target CML cells

Leukemia volume 27, pages 1201–1204 (2013)Cite this article

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Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib and dasatinib, are currently approved for the treatment of newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) patients. Although these drugs result in excellent responses in most patients, significant interpatient variability in overall response is observed. We have previously demonstrated that the degree of kinase inhibition achieved in vitro and in vivo is a critical variable of imatinib response1, 2 in CP-CML patients, and that the degree of kinase inhibition mediated is closely related to the intracellular concentration of the drug achieved.3 Importantly, the intracellular drug concentration is a result of the net effects of drug influx/efflux and plasma concentration, which can be influenced by many factors including concomitant therapies.

TKIs are generally well tolerated, however, side effects have been reported some of which, such as gastrointestinal problems, necessitate therapeutic intervention. Although the use of proton pump inhibitors (PPIs), including pantoprazole, esomeprazole and others, is contraindicated in patients taking dasatinib (at the direction of Bristol-Myers Squibb (BMS) due to the risk of reduced dasatinib exposure), they are widely prescribed in the greater community, and also frequently taken by patients on imatinib and nilotinib to control the documented gastric side effects. Data from the recent ENESTnd study indicated that up to 24% of patients treated with nilotinib concurrently received PPIs or H2 blockers.4 Furthermore, up to 34% of patients treated on study CAMN107A2101 received these drugs, indicating that their coprescription is not uncommon.4

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Acknowledgements

This work was supported by a Translational Grant from the Leukemia Lymphoma Society of USA. Imatinib and nilotinib along with their 14-C-labeled variants were kindly provided by Novartis (Basel). Laura N Eadie is a PhD Scholar funded by the Leukemia Foundation of Australia.

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Authors and Affiliations

  1. Department of Hematology, SA Pathology (RAH Campus), Adelaide, Australia

    D L White, L N Eadie, V A Saunders, D K Hiwase & T P Hughes

  2. Centre for Cancer Biology, SA Pathology, Adelaide, Australia

    D L White, L N Eadie, V A Saunders, D K Hiwase & T P Hughes

  3. Department of Medicine, Faculty of Health Science. University of Adelaide, Adelaide, Australia

    D L White, L N Eadie, D K Hiwase & T P Hughes

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  1. D L White
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  2. L N Eadie
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Correspondence to D L White.

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Competing interests

DLW and TPH have received research funding from Novartis Oncology. TPH has received Honoraria from Novartis Oncology. The rest of the authors declare no conflict of interest.

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White, D., Eadie, L., Saunders, V. et al. Proton pump inhibitors significantly increase the intracellular concentration of nilotinib, but not imatinib in target CML cells. Leukemia 27, 1201–1204 (2013). https://doi.org/10.1038/leu.2012.295

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