Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring

Abstract

Objective: Mitotane is the drug of choice in patients with adrenocortical carcinoma. The anti-neoplastic effect is correlated with mitotane plasma levels, which render it crucial to reach and maintain the concentration above 14 mg/l. However, mitotane pharmacokinetics is poorly understood. The aim of this study was to investigate the variation in plasma mitotane levels during the day and the influence of a single morning dose. Design: A prospective case-control study was conducted to investigate the variation in plasma mitotane levels. Methods: Patients who had been treated for at least 24 weeks and had reached the therapeutic plasma level (14 mg/l) at least once were eligible. In the first group, mitotane levels were determined hourly for the duration of 8 h after administration of a single morning dose. In the second group, mitotane levels were assessed similarly without administration of a morning dose. Results: Ten patients were included in this study, and three patients participated in both groups. Median plasma level at baseline was 16.2 mg/l (range 11.3-23.3 mg/l) in the first group (nZ7) and 17.0 mg/l (13.7-23.8) in the second group (nZ6). Plasma levels displayed a median increase compared with baseline of 24% (range 6-42%) at tZ4 after morning dose and a change of 13% (range K14 to 33%) at tZ4 without morning dose (PZ0.02). Conclusion: A substantial increase in mitotane plasma levels was observed in steady-state patients within a period of 8 h after morning dosing. Without morning dose, mitotane curves showed a variable profile throughout the day. This implies that random sampling could yield incidentally high levels. For this reason, we recommend early-morning trough sampling as standard management in monitoring mitotane treatment.

Outcomes of Adjuvant Mitotane after Resection of Adrenocortical Carcinoma: A 13-Institution Study by the US Adrenocortical Carcinoma Group

“…16,34,41 Mitotane levels were not available for the entire patient population that spans 2 decades, and some of the levels that were reported were <14 mg/L. Notably, studies have cautioned that interpretation of this level can be misleading, as the serum level fluctuates greatly, depending on the timing of the blood draw, 42 and predicting the blood level based on the dosage is complex. 43 Additionally, many European studies have used the proposed European Network for the Study of Adrenal Tumors staging in analyses rather than the American Joint Committee on Cancer staging, as a SEER study has previously shown that European Network for the Study of Adrenal Tumors staging better discriminates between stage II and III patients.…”

European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors

“…Reasoning: As long as mitotane plasma levels are increasing and have not yet reached a plateau at >14 mg/L, mitotane plasma levels will be assessed every 3-4 weeks. Mitotane plasma level determination is best done as morning trough sampling, at least 12 h after the last dose, preventing false high levels (267). When mitotane plasma levels have reached a plateau, it is usually sufficient to measure blood levels every 6-12 weeks.…”

Role of Mitotane in Adrenocortical Carcinoma – Review and State of the art

“…For this reason, trough sampling is considered the standard management in monitoring mitotane levels and early morning appears the optimum time to assess trough levels. 45 …”