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

Abstract

Mitotane is a key drug for the treatment of adrenal cortical carcinoma. Due to its narrow therapeutic window, 14–20 μg/mL, monitoring its concentration is crucially important. In this study, a simplified method for measuring mitotane in plasma using gas chromatography‐electron ionization‐mass spectrometry (GC‐EI‐MS) was developed. Through deproteination and liquid–liquid extraction, mitotane and an internal standard (IS) were extracted from plasma samples. GC‐EI‐MS yielded retention times of 8.2 and 8.7 min, for mitotane and the IS, respectively, with a total run time of 12 min. Selectivity and intra‐/inter‐batch accuracy and precision analyses provided a lower limit of quantification of 0.25 μg/mL, and a calibration curve between 0.25 and 40 μg/mL had good linearity (coefficient of determination = 0.992). The matrix effect factor and percent recovery of the method had good precision. Additionally, long‐term sample stability was observed below 4°C. In a clinical setting, mitotane levels in plasma from an adrenal cortical carcinoma patient were within calibration range. Therefore, this simplified method can be applied to routine therapeutic drug monitoring of mitotane, which may contribute to improved treatment of adrenal cortical carcinoma.

Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma

“…In previous studies, there has been conflicting evidence regarding potential pharmacologic activity of mitotane's metabolites, but the most recent data tends to dismiss the relevance of metabolites' activity in ACC treatment and monitoring [17][18][19]. For this reason, metabolites' measurement is not routinely performed in medical laboratories and is not expected to have any impact on adrenal function [20].…”

Ferroptosis‐based molecular prognostic model for adrenocortical carcinoma based on least absolute shrinkage and selection operator regression

“…However, a narrow therapeutic window and endocrine side effects restrict the clinical use of these drugs. 29 , 30 Thus, there is an urgent need to identify drug targets and develop new therapeutic strategies to treat ACC.…”

“…For advanced ACC, a combination of mitotane with a cytotoxic regimen of etoposide, doxorubicin, and cisplatin (EDP‐M) is recommended. However, a narrow therapeutic window and endocrine side effects restrict the clinical use of these drugs 29,30 …”

Simultaneous determination of mitotane, its metabolite, and five steroid hormones in urine samples by capillary electrophoresis using β‐CD2SDS1 complexes as hydrophobic compounds solubilizers

“…Ando et al. developed the determination of mitotane in blood plasma samples by GC in combination with electron ionization‐MS [11]. Thus far, electrophoretic method has not been developed for o, p”‐DDD and its metabolites; moreover, the simultaneous determination of mitotane and steroid hormones has not been obtained as well.…”

“…Several methods for the determination of mitotane have already been developed using HPLC [6,7], combined with liquid-liquid extraction [8], and SPE [9,10] (see Table 1). Ando et al developed the determination of mitotane in blood plasma samples by GC in combination with electron ionization-MS [11]. Thus far, electrophoretic method has not been developed for o, p"-DDD and its metabolites; moreover, the simultaneous determination of mitotane and steroid hormones has not been obtained as well.…”