Cazaubon Yoann, Talineau Yohann, Feliu Catherine, Konecki Céline, Russello Jennifer, Mathieu Olivier, Djerada Zoubir
Department of Medical Pharmacology, EA3801, SFR Cap-Santé, Reims University Hospitals, 51100 Reims, France.
Department of Medical Pharmacology, Montpellier University Hospitals, 34000 Montpellier, France.
Pharmaceutics. 2019 Oct 31;11(11):566. doi: 10.3390/pharmaceutics11110566.
Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2-3 g/day and should be slightly increased to reach the therapeutic index of 14-20 mg/L. This study developed a population PK model for mitotane and to simulate recommended/high dosing regimens. We retrospectively analyzed the data files of 38 patients with 503 plasma concentrations for the pharmacokinetic analysis. Monolix version 2019R1 was used for non-linear mixed-effects modelling. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA ≥ 14 mg/L) at one month and at three months. Mitotane concentration data were best described by a linear one-compartment model. The estimated PK parameters (between-subject variability) were: 8900 L (90.4%) for central volume of distribution (V) and 70 L·h (29.3%) for clearance (Cl). HDL, Triglyceride (Tg) and a latent covariate were found to influence Cl. The PTA at three months for 3, 6, 9, and 12 g per day was 10%, 55%, 76%, and 85%, respectively. For a loading dose of 15 g/day for one month then 5 g/day, the PTA in the first and third months was 57 and 69%, respectively. This is the first PKpop model of mitotane highlighting the effect of HDL and Tg covariates on the clearance as well as a subpopulation of ultrafast metabolizer. The simulations suggest that recommended dose regimens are not enough to target the therapeutic threshold in the third month.
米托坦是肾上腺皮质癌术后治疗中最有效的药物。对于成年人，起始剂量为2 - 3克/天，应适当增加剂量以达到14 - 20毫克/升的治疗指数。本研究建立了米托坦的群体药代动力学模型，并模拟推荐/高剂量给药方案。我们回顾性分析了38例患者的503份血浆浓度数据文件用于药代动力学分析。使用Monolix 2019R1版本进行非线性混合效应建模。进行蒙特卡洛模拟以评估1个月和3个月时达到目标（血浆浓度≥14毫克/升）的概率。米托坦浓度数据最好用线性单室模型描述。估计的药代动力学参数（个体间变异性）为：中央分布容积（V）8900升（90.4%），清除率（Cl）70升·小时（29.3%）。发现高密度脂蛋白（HDL）、甘油三酯（Tg）和一个潜在协变量会影响清除率。每天3克、6克、9克和12克剂量在3个月时达到目标的概率分别为10%、55%、76%和85%。对于先每天15克负荷剂量持续1个月然后每天5克的方案，第1个月和第3个月达到目标的概率分别为57%和69%。这是首个米托坦的群体药代动力学模型，突出了HDL和Tg协变量对清除率的影响以及超快代谢者亚群。模拟结果表明，推荐剂量方案在第3个月不足以达到治疗阈值。
