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Effect of CYP3A4 inducer dexamethasone on hepatotoxicity of lapatinib: clinical and in vitro evidence

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Abstract

Concomitant usage of lapatinib, a cytochrome P450 (CYP) 3A4 substrate and dexamethasone, a CYP3A4 inducer, is a pharmacokinetic drug–drug interaction. This combination may increase the formation of reactive lapatinib metabolites, which is potentially hepatotoxic. This study aims to evaluate the clinical effect of dexamethasone on incidence of hepatotoxicity and to ascertain its in vitro role using a parallel cell culture model experimental setup. Clinical effects of dexamethasone on lapatinib-induced hepatotoxicity were evaluated in a nested case–control study based on 120 patient data obtained from our records. For the in vitro experiment, metabolically competent transforming growth factor α mouse hepatocytes (TAMH) were treated with lapatinib and viabilities were compared in the presence or absence of dexamethasone. After adjusting for confounders, patients receiving the combination were 4.57 times (95% CI 1.23–16.88, p = 0.02) more likely to develop hepatotoxicity and 3.48 times (95% CI 1.24–9.80, p = 0.02) more likely to develop a clinically important change in alanine aminotransferase than compared to the other group. Treatment of TAMH cells with lapatinib and dexamethasone caused a further reduction in viability, as compared to treatment with lapatinib alone. At 5 μM lapatinib, the introduction of dexamethasone 20 μM produced a 59% decline in viability. This is the first study to document a clinically important interaction between lapatinib and dexamethasone, which associates with an increased occurrence of hepatotoxicity. The in vitro findings have provided substantiating evidence and insights on the role of dexamethasone in lapatinib-induced hepatotoxicity.

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Acknowledgments

The authors would like to dedicate this manuscript to Professor Emeritus Sidney Nelson for his mentorship and guidance in this study.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore

    Yi Ling Teo, Eric Chun Yong Chan, Han Kiat Ho & Alexandre Chan

  2. Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, Thailand

    Manit Saetaew

  3. Clinical Pharmacy Division, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand

    Suthan Chanthawong

  4. Department of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore

    Yoon Sim Yap

  5. Department of Oncology Pharmacy, National Cancer Centre Singapore, Singapore, Singapore

    Alexandre Chan

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  1. Yi Ling Teo
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Correspondence to Alexandre Chan.

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Teo, Y.L., Saetaew, M., Chanthawong, S. et al. Effect of CYP3A4 inducer dexamethasone on hepatotoxicity of lapatinib: clinical and in vitro evidence. Breast Cancer Res Treat 133, 703–711 (2012). https://doi.org/10.1007/s10549-012-1995-7

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  • DOI: https://doi.org/10.1007/s10549-012-1995-7

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