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Pharmacogenomics

UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia

Leukemia volume 21, pages 2311–2315 (2007)Cite this article

Abstract

Nilotinib is a novel BCR-ABL inhibitor with significantly improved potency and selectivity over imatinib. In Phase I and Phase II clinical studies of nilotinib in patients with a variety of leukemias, infrequent instances of reversible, benign elevation of bilirubin were observed. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) glucuronidates bilirubin in humans, and a polymorphism in the promoter of the gene that encodes it has been associated with hyperbilirubinemia during treatment with a number of drugs. Pharmacogenetic analysis of that TA-repeat polymorphism found an association between the (TA)7/(TA)7 genotype and risk of hyperbilirubinemia in Phase I patients with imatinib-resistant/intolerant chronic myeloid leukemia (CML) or relapsed/refractory Ph+ acute lymphoblastic leukemia (ALL); this result was replicated in two separate analyses of the chronic phase (CP) and accelerated phase (AP) CML arms of a Phase II study. As nilotinib is not known to be glucuronidated by UGT1A1, the combined impact of inhibition of UGT1A1 activity by nilotinib and genetic polymorphism is the most likely cause of the increased rate of hyperbilirubinemia.

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Acknowledgements

In addition to those investigators listed as authors, Kapil Bhala participated as an investigator in this trial. We thank Wade Brown, Elisabeth Leroy and Michele Gysen for their management of sample collection and genotyping. This study was supported by research funding from Novartis Pharmaceuticals. Work was performed at Novartis Institutes for Biomedical Research and Novartis Pharmaceuticals.

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Authors and Affiliations

  1. Clinical Pharmacogenetics, Novartis Institutes for Biomedical Research, Cambridge, MA, USA

    J B Singer & J M Meyer

  2. Oncology Global Development, Novartis Pharmaceuticals, Florham Park, NJ, USA

    Y Shou, Y Hsu, A S Robeva, P Rae, A Weitzman & M Dugan

  3. Leukemia Department, MD Anderson Cancer Center, Houston, TX, USA

    F Giles & H M Kantarjian

  4. Department of Hematology/Oncology, Johann Wolfgang Goethe-Universität, Frankfurt, Germany

    O G Ottmann

Authors
  1. J B Singer
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  2. Y Shou
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  3. F Giles
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  4. H M Kantarjian
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  6. A S Robeva
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  7. P Rae
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  8. A Weitzman
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  9. J M Meyer
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  10. M Dugan
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  11. O G Ottmann
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Correspondence to J B Singer.

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Singer, J., Shou, Y., Giles, F. et al. UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia. Leukemia 21, 2311–2315 (2007). https://doi.org/10.1038/sj.leu.2404827

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  • DOI: https://doi.org/10.1038/sj.leu.2404827

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