Wang Hechuan, Long-Boyle Janel, Winger Beth Apsel, Nicolaides Theodore, Mueller Sabine, Prados Michael, Ivaturi Vijay
Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.
Department of Pediatrics, Division of Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California, USA.
J Clin Pharmacol. 2020 Sep;60(9):1209-1219. doi: 10.1002/jcph.1617. Epub 2020 May 31.
Vemurafenib (Zelboraf) is an orally available BRAF inhibitor approved for the treatment of unresectable or metastatic BRAF -mutant melanoma. The primary objective of this work was to characterize the pharmacokinetics (PK) of vemurafenib in pediatric patients with recurrent/refractory astrocytomas harboring the BRAF mutation. The study was also designed to evaluate the feasibility of replacing whole vemurafenib tablets with crushed tablets in young children unable to swallow tablets. Twenty-five pediatric patients (median age, 8.8 years; range, 3.3-19.2) with recurrent/refractory BRAF -mutant astrocytomas received whole (n = 19) or crushed (n = 6) vemurafenib tablets twice daily. Plasma samples were collected on days 1, 15, and 22 in cycle 1 of vemurafenib treatment. Descriptive PK analyses demonstrated significant variability (approximately 6-fold) in drug exposure. A 1-compartment model with first-order absorption and elimination was developed by adjusting the vemurafenib PK model previously validated in adults with mutant BRAF melanoma. After inclusion of allometric scaling on total body weight, the model adequately described the PK of vemurafenib in children between a wide age range of 3 to 19 years old. In the crushed-tablet cohort, relative bioavailability was approximately 96% (95% confidence interval, 49%-142%) compared to that seen in pediatric patients receiving whole tablets based on the preliminary comparison analysis results. Moderate intrapatient variability (48%) of vemurafenib clearance was observed. There was significant correlation (R = 0.83) between area under the plasma concentration-time curve and trough concentration at steady state. These results will help increase the number of pediatric patients for whom vemurafenib is accessible and facilitate improved dosing in pediatric patients with recurrent/refractory BRAF astrocytomas.
维莫非尼（佐博伏）是一种口服可用的BRAF抑制剂，被批准用于治疗不可切除或转移性BRAF突变型黑色素瘤。这项工作的主要目的是描述维莫非尼在患有BRAF突变的复发性/难治性星形细胞瘤儿科患者中的药代动力学（PK）特征。该研究还旨在评估在无法吞咽片剂的幼儿中用碾碎的片剂替代整片维莫非尼片剂的可行性。25例患有复发性/难治性BRAF突变型星形细胞瘤的儿科患者（中位年龄8.8岁；范围3.3 - 19.2岁）每天两次接受整片（n = 19）或碾碎（n = 6）的维莫非尼片剂。在维莫非尼治疗的第1周期的第1天、第15天和第22天采集血浆样本。描述性PK分析显示药物暴露存在显著变异性（约6倍）。通过调整先前在BRAF突变型黑色素瘤成人患者中验证的维莫非尼PK模型，建立了具有一级吸收和消除的单室模型。纳入基于总体重的异速生长比例缩放后，该模型充分描述了3至19岁广泛年龄范围内儿童维莫非尼的PK。根据初步比较分析结果，与接受整片片剂的儿科患者相比，碾碎片剂队列中的相对生物利用度约为96%（95%置信区间，49% - 142%）。观察到维莫非尼清除率存在中度患者内变异性（48%）。血浆浓度 - 时间曲线下面积与稳态谷浓度之间存在显著相关性（R = 0.83）。这些结果将有助于增加可使用维莫非尼的儿科患者数量，并促进对患有复发性/难治性BRAF星形细胞瘤的儿科患者进行更优化的给药。
