比较干血斑与血浆浓度在儿童中用于监测白消安治疗药物浓度。

Comparing Dried Blood Spots and Plasma Concentrations for Busulfan Therapeutic Drug Monitoring in Children.

机构信息

Clinical Pharmacology and Toxicology Unit, Geneva University Hospitals, University of Geneva.

Division of Hematology, Department of Oncology, Geneva University Hospitals.

出版信息

Ther Drug Monit. 2020 Feb;42(1):111-117. doi: 10.1097/FTD.0000000000000673.

DOI:10.1097/FTD.0000000000000673

PMID:31348116

Abstract

BACKGROUND

Busulfan (Bu) is one of the conditioning regimen components for pediatric hematopoietic stem cell transplantation. Bu therapeutic drug monitoring (TDM) is essential for a successful treatment outcome and toxicity evasion. Dried blood spot (DBS) sampling is a rapid and simple method for Bu TDM, compared with conventional plasma sampling. This study evaluated the feasibility of using the DBS method for Bu TDM. The hematocrit (Hct) and conditioning day were also examined for their impact on the DBS method's performance.

METHODS

Venous blood collected from 6 healthy volunteers was diluted, using their plasma into 4 samples of varying Hct values. Each sample was spiked with Bu calibrators (300, 600, and 1400 ng/mL), prepared using DBS and dried plasma spot (DPS) sampling and analyzed using a validated liquid-chromatography tandem-mass spectrometry method. Clinical blood samples (n = 153) from pediatric patients (n = 15) treated with Bu (mainly from doses 1, 2, 5, and 9) were used to prepare paired volumetric DBS and DPS samples. A Bland-Altman plot and Deming regression were used to define the agreement between the paired DBS and DPS measurements. Passing-Bablok regression analyses investigated the effects of Hct and conditioning day on the linearity between both methods.

RESULTS

In vitro analyses showed good agreement between DBS and DPS measurements, with a mean difference of -5.4% and a 95% confidence interval on the limits of agreement of -15.3% to 4.6%. Clinical samples showed good correlation (Pearson correlation coefficient = 0.96; slope = 1.00) between the DBS and DPS methods. The DBS method met the clinical acceptance limits for clinical samples, with a bias <±20%. Bland-Altman plots showed good agreement, with only 5.8% of paired measurements exceeding the limits of agreement (±1.96 SD), although within its 95% confidence interval. Hct observations ranged from 21.7% to 34.7% and did not affect Bu concentrations measured from DBS in either the in vitro or in vivo studies.

CONCLUSIONS

These results show that DBS is a useful method for Bu TDM, provided samples are analyzed on the collection day. DBS sampling offers advantages over traditional plasma sampling in infants and younger children because only small volumes of blood are required.

摘要

背景

白消安（Bu）是儿科造血干细胞移植的一种预处理方案成分。Bu 治疗药物监测（TDM）对于成功的治疗结果和避免毒性至关重要。与传统的血浆取样相比，干血斑（DBS）取样是一种快速简单的 Bu TDM 方法。本研究评估了使用 DBS 方法进行 Bu TDM 的可行性。还检查了血细胞比容（Hct）和预处理日对 DBS 方法性能的影响。

方法

从 6 名健康志愿者采集静脉血，用其血浆稀释成 4 个具有不同 Hct 值的样本。每个样本均用 Bu 校准剂（300、600 和 1400ng/ml）进行了加标，采用 DBS 和干血浆斑（DPS）取样制备，并采用经过验证的液相色谱-串联质谱法进行了分析。使用来自接受 Bu 治疗的儿科患者（n=15）的临床血液样本（n=15）（主要来自剂量 1、2、5 和 9）制备配对的体积 DBS 和 DPS 样本。采用 Bland-Altman 图和 Deming 回归来定义配对 DBS 和 DPS 测量值之间的一致性。通过 Passing-Bablok 回归分析研究了 Hct 和预处理日对两种方法之间线性关系的影响。

结果

体外分析显示 DBS 和 DPS 测量值之间具有良好的一致性，平均差异为-5.4%，在一致性界限的 95%置信区间为-15.3%至 4.6%。临床样本显示 DBS 和 DPS 方法之间具有良好的相关性（Pearson 相关系数=0.96；斜率=1.00）。DBS 方法满足临床样本的临床可接受限值，偏差<±20%。Bland-Altman 图显示了良好的一致性，只有 5.8%的配对测量值超出了一致性界限（±1.96SD），尽管在其 95%置信区间内。Hct 观察值范围为 21.7%至 34.7%，并且在体外和体内研究中均未影响从 DBS 测量的 Bu 浓度。