Kerkhofs T M A, Derijks L J J, Ettaieb M H T, Eekhoff E M W, Neef C, Gelderblom H, den Hartigh J, Guchelaar H J, Haak H R
Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands
Department of Internal MedicineMáxima Medical Center, Ds. Th. Fliednerstraat 1, Eindhoven/Veldhoven 5631, The NetherlandsDepartment of Clinical PharmacologyMáxima Medical Center, Eindhoven/Veldhoven, The NetherlandsSection EndocrinologyDepartment of Internal Medicine, VU Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsDepartment of Clinical Pharmacy and ToxicologyMaastricht University Medical Center+, Maastricht, The NetherlandsDepartment of Health Services Research and CAPHRI School for Public Health and Primary CareMaastricht University, Maastricht, The NetherlandsDepartments of Clinical OncologyClinical Pharmacy and ToxicologyLeiden University Medical Center, Leiden, The NetherlandsDivision of General Internal MedicineDepartment of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands.
Eur J Endocrinol. 2014 Dec;171(6):677-83. doi: 10.1530/EJE-14-0388. Epub 2014 Sep 8.
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.
A prospective case-control study was conducted to investigate the variation in plasma mitotane levels.
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.
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 (n=7) and 17.0 mg/l (13.7-23.8) in the second group (n=6). Plasma levels displayed a median increase compared with baseline of 24% (range 6-42%) at t=4 after morning dose and a change of 13% (range -14 to 33%) at t=4 without morning dose (P=0.02).
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.
米托坦是肾上腺皮质癌患者的首选药物。其抗肿瘤作用与米托坦血浆水平相关，因此达到并维持浓度高于14mg/L至关重要。然而，米托坦的药代动力学尚不清楚。本研究旨在调查一天中血浆米托坦水平的变化以及单次晨起剂量的影响。
进行一项前瞻性病例对照研究以调查血浆米托坦水平的变化。
曾接受至少24周治疗且至少有一次达到治疗性血浆水平（14mg/L）的患者符合条件。第一组在单次晨起给药后8小时内每小时测定米托坦水平。第二组在不给予晨起剂量的情况下进行类似的米托坦水平评估。
本研究纳入10名患者，3名患者参与了两组。第一组（n = 7）基线时血浆水平中位数为16.2mg/L（范围11.3 - 23.3mg/L），第二组（n = 6）为17.0mg/L（13.7 - 23.8）。晨起给药后t = 4时，血浆水平与基线相比中位数增加24%（范围6 - 42%），未给予晨起剂量时t = 4时变化为13%（范围 - 14至33%）（P = 0.02）。
在晨起给药后8小时内，稳态患者的米托坦血浆水平显著升高。不给予晨起剂量时，米托坦曲线在一天中呈现出可变的特征。这意味着随机采样可能偶然产生高水平。因此，我们建议将清晨低谷采样作为监测米托坦治疗的标准管理方法。
