Ouellet Daniele, Kassir Nastya, Chiu Joannellyn, Mouksassi Mohamad-Samer, Leonowens Cathrine, Cox Donna, DeMarini Douglas J, Gardner Olivia, Crist Wendy, Patel Kiran
GlaxoSmithKline, Research Triangle Park, NC, USA.
Janssen Research & Development, Spring House, PA, USA.
Cancer Chemother Pharmacol. 2016 Apr;77(4):807-17. doi: 10.1007/s00280-016-2993-y. Epub 2016 Mar 3.
To characterize the pharmacokinetics of oral trametinib, a first in class MEK inhibitor, identify covariates, and describe the relationship between exposure and clinical effects in patients with BRAF V600 metastatic melanoma.
Trametinib concentrations obtained in three clinical studies were included in the population pharmacokinetic analysis. Trametinib 2 mg once daily was administered in the Phase 2 and 3 studies. The impact of exposure [trough (C min) or average concentration] on response rates and progression-free survival (PFS) was examined.
Plasma concentrations (n = 3120) obtained in 493 patients were described using a two-compartment model. Trametinib oral clearance was lower in women relative to men (1.26-fold) and increased with body weight. There was no significant effect of age, mild or moderate renal impairment, or mild hepatic impairment on oral clearance. Between-subject variability was low (24 %). The number of responders was consistent across median exposure range, although tended to be lower at trough concentration <10 ng/mL. Disease stage was found to be a significant predictor of response with a lower response rate in patients with disease stage of M1c. Lactate dehydrogenase was significant in the analysis of PFS. Patients with observed C min above the median had longer PFS than those below median based on Phase 2 study (median 10.6 ng/mL), while the effect of exposure was not statistically significant in the Phase 3 study (median 13.6 ng/mL).
No dosage adjustments are required with any of the covariates tested. Clinical efficacy was associated with trametinib trough concentrations greater than 10 ng/mL.
表征口服曲美替尼（首个MEK抑制剂）的药代动力学，识别协变量，并描述BRAF V600转移性黑色素瘤患者中暴露与临床效应之间的关系。
三项临床研究中获得的曲美替尼浓度纳入群体药代动力学分析。在2期和3期研究中，每日一次给予曲美替尼2mg。研究了暴露量[谷浓度（Cmin）或平均浓度]对缓解率和无进展生存期（PFS）的影响。
使用二室模型描述了493例患者的血浆浓度（n = 3120）。女性的曲美替尼口服清除率低于男性（1.26倍），且随体重增加。年龄、轻度或中度肾功能损害或轻度肝功能损害对口服清除率无显著影响。个体间变异性较低（24%）。在中位暴露范围内，缓解者数量一致，尽管在谷浓度<10ng/mL时往往较低。发现疾病分期是缓解的重要预测因素，M1c期疾病患者的缓解率较低。乳酸脱氢酶在PFS分析中具有显著性。根据2期研究（中位值10.6ng/mL），观察到Cmin高于中位值的患者的PFS长于低于中位值的患者，而在3期研究（中位值13.6ng/mL）中，暴露量的影响无统计学显著性。
对所测试的任何协变量均无需调整剂量。临床疗效与曲美替尼谷浓度大于10ng/mL相关。
