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A method for the minimally invasive drug monitoring of mitotane by means of volumetric absorptive microsampling for a home-based therapeutic drug monitoring

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Abstract

Mitotane is the only currently approved treatment for adrenocortical carcinoma (ACC), a rare endocrine malignancy. Plasma levels within the range of 14 to 20 mg L−1 are correlated with higher clinical efficacy and manageable toxicity. Because of this narrow therapeutic index and slow pharmacokinetics, therapeutic drug monitoring is an essential element of mitotane therapy. A small step towards the therapeutic drug monitoring (TDM) by volumetric absorptive microsampling (VAMS) was made with this work. A simple method enabling the patient to collect capillary blood at home for the control of mitotane blood concentration was developed and characterized using MITRA™ VAMS 20 μL microsampler. Dried blood samples were extracted prior to HPLC-UV analysis. Mitotane and the internal standard dicofol (DIC) were detected at 230 nm by ultra-violet detection after separation on a C8 reversed phase column. The assay was validated in the range of 1 to 50 mg L−1. Dried samples were stable at room temperature and at 2–8 °C for 1 week. At 37 °C, a substantial amount of the analyte was lost probably due to evaporation. Hematocrit bias, a common problem of conventional dried blood techniques, was acceptable in the tested range. However, a significant difference in recovery from spiked and authentic patient blood was detected. Comparison of mitotane concentration in dried blood samples (CDBS) by VAMS with venous plasma in patients on mitotane therapy demonstrated poor correlation of CDBS with the concentration in plasma (CP). In conclusion, application of VAMS in clinical routine for mitotane TDM appears to be of limited value in the absence of a method-specific target range.

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Funding

This study was funded by Horphag Research (Europe) Ltd. and in part by the German Research Council (DFG, German Research Foundation) Projektnummer: 314061271 – TRR 205 as well as by an individual grant to M.F. (FA466/4-2) and M.K. (KR4371/1-2).

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Authors and Affiliations

  1. Institute for Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074, Würzburg, Germany

    Bettina Friedl & Oliver Scherf-Clavel

  2. Department of Internal Medicine I, Division of Endocrinology/Diabetology, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Germany

    Max Kurlbaum, Matthias Kroiss & Martin Fassnacht

  3. Central Laboratory, Clinical Chemistry and Laboratory Medicine, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Germany

    Max Kurlbaum

  4. Comprehensive Cancer Center, University of Würzburg, Josef-Schneider-Str. 6, 97080, Würzburg, Germany

    Matthias Kroiss & Martin Fassnacht

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  1. Bettina Friedl
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  2. Max Kurlbaum
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Correspondence to Oliver Scherf-Clavel.

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This study was part of the European Network for the Study of Adrenal Tumors (ENSAT) registry, which has been approved by the ethics committee of the University of Würzburg (approval number 86/03 and 88/11).

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Friedl, B., Kurlbaum, M., Kroiss, M. et al. A method for the minimally invasive drug monitoring of mitotane by means of volumetric absorptive microsampling for a home-based therapeutic drug monitoring. Anal Bioanal Chem 411, 3951–3962 (2019). https://doi.org/10.1007/s00216-019-01868-1

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