Effting Cristiane, de Moraes Arantes Adriano, Queiroz Labre Luciana V, Carneiro Wilsione J, de Oliveira Neto Jerônimo R, Bariani César, Rodrigues Caroline R, Rodrigues Andryne R, Cunha Luiz C
*Núcleo de Estudos e Pesquisas Tóxico-Farmacológicas, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia; †Departamento de Farmácia, Universidade Estadual de Goiás, Anápolis; and ‡Unidade de Transplante de Medula Óssea do Hospital Araújo Jorge, Goiânia, Brazil.
Ther Drug Monit. 2015 Feb;37(1):66-70. doi: 10.1097/FTD.0000000000000106.
Busulfan is an alkylating agent used for conditioning patients undergoing hematopoietic stem cell transplantation with a narrow therapeutic range and highly variable pharmacokinetics. High concentrations induce toxicity, especially hepatic veno-occlusive disease, also referred to as sinusoidal obstruction syndrome. This study aimed to assess busulfan pharmacokinetic variability in pretransplant conditioning regimens using an analytical method validated by high-performance liquid chromatography coupled to diode array detector (HPLC/PDA).
Eight patients who used the test dose (TD) of 1 mg/kg busulfan 10 days before conditioning were included, and 10 serial blood samples were collected to determine: the elimination half-life (t1/2), total area under the curve (AUCT), total clearance (Cl(T)/F), and plasma concentration at steady state (C(ss)), using a monocompartmental model and first-order kinetics. The instrumental conditions were: HPLC/PDA Shimadzu, column ACE C18 (150 mm × 4 mm); methanol/water/acetonitrile (65:20:15) eluent flow rate of 1 mL/min; 1,6-bis-(methanesulfonyloxy)-hexane; UV λ = 276 nm; analysis time 17 minutes; and derivatization with sodium diethylcarbamate. The dose was adjusted, and 4 blood samples per day were collected at days 2, 3, and 4 of treatment for new plasma determinations.
Four patients needed higher doses; the mean dose administered was 1.02 ± 0.19 mg/kg. Mean results at TD: t1/2 = 2.88 ± 0.5 hours; Cl(T)/F = 0.18 ± 0.03 L · h(-1) · kg(-1); AUC(T) = 5461.00 ± 961.15 ng · mL(-1) · h(-1); and C(ss) = 911.3 ± 159.8 ng/mL. Mean results of samples collected during conditioning: t1/2 = 3.21 ± 0.9 hours; Cl(T)/F = 0.13 ± 0.02 L · h(-1) · kg(-1); AUC(T) = 7571 ± 1705 ng · mL(-1) · h(-1); and C(ss) = 1262.0 ± 284.3 ng/mL.
High variability in the assessed pharmacokinetic parameters was observed, with a 38% variation in C(ss) between TD and conditioning regimen; Cl(T)/F decreased by 30%, suggesting drug accumulation after multiple-dose regimen. Although being lower than reported in the literature, this variation may be associated with toxicity of the proposed treatment, justifying patient monitoring and enhancing validity of previous pharmacokinetic evaluation using TD regimen.
白消安是一种烷化剂，用于造血干细胞移植患者的预处理，其治疗窗狭窄，药代动力学高度可变。高浓度会诱发毒性，尤其是肝静脉闭塞病，也称为窦性阻塞综合征。本研究旨在使用高效液相色谱-二极管阵列检测器（HPLC/PDA）验证的分析方法，评估预处理方案中白消安的药代动力学变异性。
纳入8例在预处理前10天使用1mg/kg白消安试验剂量（TD）的患者，并采集10份系列血样，采用单室模型和一级动力学来确定消除半衰期（t1/2）、曲线下总面积（AUCT）、总清除率（Cl(T)/F）和稳态血浆浓度（C(ss)）。仪器条件为：岛津HPLC/PDA，ACE C18柱（150mm×4mm）；甲醇/水/乙腈（65:20:15）洗脱液流速为1mL/min；1,6-双（甲磺酰氧基）己烷；紫外波长λ=276nm；分析时间17分钟；用二乙基氨基甲酸钠衍生化。调整剂量后，在治疗的第2、3和4天每天采集4份血样进行新的血浆测定。
4例患者需要更高剂量；平均给药剂量为1.02±0.19mg/kg。TD时的平均结果：t1/2=2.88±0.5小时；Cl(T)/F=0.18±0.03L·h(-1)·kg(-1)；AUC(T)=5461.00±961.15ng·mL(-1)·h(-1)；C(ss)=911.3±159.8ng/mL。预处理期间采集样本的平均结果：t1/2=3.21±0.9小时；Cl(T)/F=0.13±0.02L·h(-1)·kg(-1)；AUC(T)=7571±1705ng·mL(-1)·h(-1)；C(ss)=1262.0±284.3ng/mL。
观察到评估的药代动力学参数存在高度变异性，TD与预处理方案之间C(ss)的变异为38%；Cl(T)/F下降了30%，表明多剂量方案后药物蓄积。尽管低于文献报道，但这种变异可能与所提议治疗的毒性相关，这为患者监测提供了依据，并提高了先前使用TD方案进行药代动力学评估的有效性。
