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

Abstract

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 14-20 mg L 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 100 μL of plasma. The supernatant was submitted to liquid chromatography coupled with ultra-violet detection at 230 nm. Mitotane retention time was 7.1 min. The limit of detection was 0.1 mg L and the limit of quantification was 0.78 mg L . The assay demonstrated a linear range of 0.78-25 mg L with correlation coefficients (r ) 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.

A simplified method for therapeutic drug monitoring of mitotane by gas chromatography‐electron ionization‐mass spectrometry

“…Based on selectivity, calibration curve linearity, and variability, 0.25 μg/mL was established as the lower limit of quantification (LLOQ) of the method. It should be noted that the calibration range and LLOQ obtained are superior to those of previously reported methods (Andersen et al, ; Benecke et al, ; De Francia et al, ; Feliu et al, ; Garg et al, ; Inouye et al, ; Mornar, Sertić, Turk, Nigović, & Koršić, ).…”

“…Considering the fast‐paced clinical requirements, these conditions are not applicable for routine TDM of mitotane. Furthermore, a measurement method involving a simplified sample preparation procedure has been recently reported by Feliu et al (); however, this method involves the use of an ultra‐high performance LC (UPLC) system, which may currently be less common than LC or GC systems, although UPLC may be more available in future decades. In addition, this procedure does not involve the use of an internal standard (IS), which creates the difficulty of judging whether the observation of a low mitotane peak is due to a low rate of extraction or a low presence of mitotane.…”

Population Pharmacokinetics Modelling and Simulation of Mitotane in Patients with Adrenocortical Carcinoma: An Individualized Dose Regimen to Target All Patients at Three Months?

“…Mitotane was identified and quantified in plasma by liquid chromatography (ultraviolet method) [25].…”