Nijenhuis Cynthia M, Huitema Alwin D R, Marchetti Serena, Blank Christian, Haanen John B A G, van Thienen Johannes V, Rosing Hilde, Schellens Jan H M, Beijnen Jos H
Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek/The Netherlands Cancer Institute and MC Slotervaart, Amsterdam, The Netherlands.
Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
J Clin Pharmacol. 2016 Oct;56(10):1307-12. doi: 10.1002/jcph.728. Epub 2016 Apr 8.
Pharmacokinetic monitoring is increasingly becoming an important part of clinical care of tyrosine kinase inhibitor treatment. Vemurafenib is an oral tyrosine kinase inhibitor that inhibits mutated serine/threonine protein kinase B-Raf (BRAF) and is approved for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The aim of this study was to establish the relationship between dried blood spot (DBS) and plasma concentrations of vemurafenib to enable the use of DBS sampling, which is a minimally invasive form of sample collection. In total, 43 paired plasma and DBS samples (in duplicate) were obtained from 8 melanoma patients on vemurafenib therapy and were analyzed using high-performance liquid chromatography-tandem mass spectrometry. Plasma concentrations were predicted from the DBS concentrations using 2 methods: (1) individual hematocrit correction and blood cell-to-plasma partitioning and (2) the calculated slope explaining the relationship between DBS and plasma concentrations (without individual hematocrit correction). Vemurafenib DBS concentrations and plasma concentrations showed a strong correlation (r = 0.964), and the relationship could be described by ([vemurafenib]plasma = [vemurafenib]DBS /0.64). The predicted plasma concentrations were within ±20% of the analyzed plasma concentrations in 97% and 100% of the samples for the methods with and without hematocrit correction, respectively. In conclusion, DBS concentrations and plasma concentrations of vemurafenib are highly correlated. Plasma concentrations can be predicted from DBS concentration using the blood cell-to-plasma partition and the average hematocrit value of this cohort (0.40 L/L). DBS sampling for pharmacokinetic monitoring of vemurafenib treatment can be used in clinical practice.
药代动力学监测正日益成为酪氨酸激酶抑制剂治疗临床护理的重要组成部分。维莫非尼是一种口服酪氨酸激酶抑制剂，可抑制突变的丝氨酸/苏氨酸蛋白激酶B-Raf（BRAF），已被批准用于治疗BRAF V600突变阳性的不可切除或转移性黑色素瘤成年患者。本研究的目的是建立维莫非尼干血斑（DBS）浓度与血浆浓度之间的关系，以便能够使用DBS采样，这是一种微创的样本采集形式。总共从8名接受维莫非尼治疗的黑色素瘤患者中获得了43对血浆和DBS样本（一式两份），并使用高效液相色谱-串联质谱法进行分析。使用两种方法从DBS浓度预测血浆浓度：（1）个体血细胞比容校正和血细胞与血浆的分配，以及（2）计算斜率以解释DBS与血浆浓度之间的关系（不进行个体血细胞比容校正）。维莫非尼DBS浓度与血浆浓度显示出强烈的相关性（r = 0.964），这种关系可以用（[维莫非尼]血浆 = [维莫非尼]DBS /0.64）来描述。对于有和没有血细胞比容校正的方法，预测的血浆浓度分别在97%和100%的样本中在分析的血浆浓度的±20%范围内。总之，维莫非尼的DBS浓度与血浆浓度高度相关。可以使用血细胞与血浆的分配以及该队列的平均血细胞比容值（0.40 L/L）从DBS浓度预测血浆浓度。用于维莫非尼治疗药代动力学监测的DBS采样可用于临床实践。
