Therapeutic drug monitoring of mitotane: Analytical assay and patient follow-up

Adrenocortical carcinoma (ACC) is an aggressive malignancy of the adrenal gland. Mitotane (o,p'-DDD) is the most effective chemotherapy for ACC. According to the literature, mitotane plasma trough concentrations within 14-20mg L-1 are correlated with a higher response rate with acceptable toxicity. Therapeutic drug monitoring (TDM) of mitotane is therefore recommended. The aim of this study was to propose a robust and simple method for mitotane quantification in plasma. The validation procedures were based on international guidelines. Sample preparation consisted of a single protein precipitation with methanol using 100L of plasma. The supernatant was submitted to liquid chromatography coupled with ultra-violet detection at 230nm. Mitotane retention time was 7.1min. The limit of detection was 0.1mg L-1 and the limit of quantification was 0.78mg L-1. The assay demonstrated a linear range of 0.78-25mg L-1 with correlation coefficients (r(2)) at 0.999. Inter- and intra-assay precision was <4.85%. Evaluation of accuracy showed a deviation <13.69% from target concentration at each quality control level. This method proved easy and rapid to perform mitotane TDM and required a small volume of sample. It was successfully applied to routine TDM in our laboratory.