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Midazolam as a phenotyping probe to predict sunitinib exposure in patients with cancer

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Abstract

Purpose

Patients treated with sunitinib show substantial inter-patient variability in drug exposure (~30–40 %), which is largely unexplained. Since sunitinib is metabolized by cytochrome P450(CYP)3A4, variability in the activity of this enzyme may explain a considerable proportion of this inter-patient variability. Midazolam is widely used as a phenotyping probe to assess CYP3A4-activity. The objective of this study was to prospectively evaluate the relationship between midazolam and sunitinib exposure. Additionally, the correlation between sunitinib trough levels and exposure and the influence of sunitinib on midazolam exposure was determined.

Methods

Thirteen patients treated with sunitinib in a 4 weeks “on”—2 weeks “off” regimen received twice 7.5 mg midazolam; once with and once without sunitinib. Steady-state sunitinib, its active metabolite SU12662 and midazolam exposures were determined.

Results

A significant correlation between midazolam exposure (AUC0–7h) and steady-state sunitinib and sunitinib + SU12662 exposure (AUC0–24h) was found (p = 0.006 and p = 0.0018, respectively); midazolam exposure explained 51 and 41 % of the inter-patient variability in sunitinib and sunitinib + SU12622 exposure. Furthermore, C trough was highly correlated (r 2 = 0.94) with sunitinib AUC0–24h. Sunitinib decreased midazolam exposure with 24 % (p = 0.034).

Conclusion

Midazolam exposure is highly correlated with sunitinib exposure and explains a large proportion of the observed inter-patient variability in sunitinib pharmacokinetics. Consequently, midazolam could be used to identify patients that are at risk of under- or overtreatment, respectively, at the start of sunitinib therapy. Moreover, sunitinib and sunitinib + SU12662 trough levels are highly correlated with drug exposure and can thus be used in clinical practice to individualize sunitinib therapy. The decrease in midazolam exposure by sunitinib needs further investigation.

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Acknowledgments

We thank Dr. Ron Wolterbeek for his statistical support. This work was supported in part by the American Lebanese Syrian Associated Charities (ALSAC).

Conflict of interest

The authors have no disclosures to declare.

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Authors and Affiliations

  1. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

    D. de Wit, J. den Hartigh, J. M. C. König-Quartel, T. Hessing & H. J. Guchelaar

  2. Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands

    H. Gelderblom & M. den Hollander

  3. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

    A. Sparreboom

  4. Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, Route 864, Postbus 9101, 6500 HB, Nijmegen, The Netherlands

    N. P. van Erp

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  1. D. de Wit
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Correspondence to N. P. van Erp.

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de Wit, D., Gelderblom, H., Sparreboom, A. et al. Midazolam as a phenotyping probe to predict sunitinib exposure in patients with cancer. Cancer Chemother Pharmacol 73, 87–96 (2014). https://doi.org/10.1007/s00280-013-2322-7

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  • DOI: https://doi.org/10.1007/s00280-013-2322-7

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