Circannual variation of mitotane and its metabolites plasma levels in patients with adrenocortical carcinoma

• Published in: Journal of pharmacy and pharmacology 2017-11, Vol.69 (11), p.1524-1530
• Main Authors: Cusato, Jessica, De Francia, Silvia, Allegra, Sarah, Carrella, Simona, Pirro, Elisa, Piccione, Francesca Maria, De Martino, Francesca, Ferrero, Anna, Daffara, Fulvia Claudia, Terzolo, Massimo, Berruti, Alfredo, Di Carlo, Francesco, Tampellini, Marco, D'Avolio, Antonio
• Format: Article
• Language: English
• Subjects: Adipose tissue; Adipose Tissue - metabolism; Adrenal Cortex Neoplasms - therapy; adrenocortical carcinoma; Adrenocortical Carcinoma - therapy; Adult; Antineoplastic Agents, Hormonal - administration & dosage; Antineoplastic Agents, Hormonal - pharmacokinetics; Bioaccumulation; Chemotherapy, Adjuvant - methods; Chromatography, High Pressure Liquid - methods; DDD; DDE; Drug dosages; Female; gender medicine; Genetic transformation; HPLC; Humans; Lipophilic; Male; Metabolites; Middle Aged; Mitotane - administration & dosage; Mitotane - analogs & derivatives; Mitotane - pharmacokinetics; Neuroendocrine tumors; Nitrous oxide; Plasma; Plasma levels; Seasons; Sex Factors; Surgery; Therapeutic Drug Monitoring; Time Factors; Tissues; Young Adult
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1111/jphp.12798

Objectives Mitotane is the reference drug for the adrenocortical carcinoma treatment; its pharmacological activity seems to depend on drug transformation in two active metabolites: o,p'‐DDE (dichlorodiphenylethene) and o,p'‐DDA (dichlorodiphenylacetate). Mitotane and metabolites are lipophilic agents; thus, they tend to accumulate into adipose tissues (white and brown), which change their prevalence seasonally. Aim of the work was to evaluate mitotane and metabolites plasma levels variation over the year, in adrenocortical cancer patients treated with Lysodren® for at least 6 months. Methods We enrolled a group of 86 adrenocortical carcinoma diagnosed patients, who underwent radical surgery and started mitotane as adjuvant treatment. For drug and metabolites plasma level (from samples collected ~12 h after the dose administration of mitotane, just before the subsequent administration) determination, a validated chromatographic method was used. Key findings Results showed an evidence of a seasonal trend for the three substance (o,p'‐DDD, o,p'‐DDE and o,p'‐DDA) plasma levels, in terms of acrophases and lower values. Furthermore, it came out that male patients need a higher significant mitotane drug dose than female patients to reach mitotane therapeutic window. Conclusions In conclusion, this is the first study assessing a mitotane plasma level variation over the year, but further studies in larger cohorts are required.