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

摘要

Mitotane is the only currently approved treatment for adrenocortical carcinoma (ACC), a rare endocrine malignancy. Plasma levels within the range of 14 to 20mgL(-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 20L microsampler. Dried blood samples were extracted prior to HPLC-UV analysis. Mitotane and the internal standard dicofol (DIC) were detected at 230nm by ultra-violet detection after separation on a C8 reversed phase column. The assay was validated in the range of 1 to 50mgL(-1). Dried samples were stable at room temperature and at 2-8 degrees C for 1week. At 37 degrees 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 (C-DBS) by VAMS with venous plasma in patients on mitotane therapy demonstrated poor correlation of C-DBS with the concentration in plasma (C-P)(.) 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.