Accurate Prediction of Initial Busulfan Exposure Using a Test Dose With 2-and 6-Hour Blood Sampling in Adult Patients Receiving a Twice-Daily Intravenous Busulfan-Based Conditioning Regimen
Accurate Prediction of Initial Busulfan Exposure Using a Test Dose With 2-and 6-Hour Blood Sampling in Adult Patients Receiving a Twice-Daily Intravenous Busulfan-Based Conditioning Regimen
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DOI：
10.1002/jcph.1354
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发表时间：
2019-05-01
影响因子：
2.9
通讯作者：
Yang, Wanhua
中科院分区：
文献类型：
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作者：
Huang, Jingjing;Li, Ziwei;Yang, Wanhua
本研究旨在使用稀疏抽样方案的测试剂量来预测接受造血细胞移植的成年患者的白花丹初始剂量的曲线下面积(AUC)。试验量为0.8 mg/kg的白消安，在静脉注射白消安调理方案前2天使用。用非房室分析方法计算试验剂量和第一剂量(AUC(T)、CLT、AUC(1)和CL1)的AUC和清除量(CL)。根据群体药代动力学模型，采用贝叶斯方法建立了试验剂量的稀疏抽样方案。通过评估平均预测误差、均方根误差、绝对平均预测误差和Bland-Altman图来确定最优稀疏抽样方案。AUC(1)平均为7.20+/-1.48 mg中心点h/L，范围为4.70~9.46 mg中心点h/L，45%(9/20)的患者AUC(1)低于7.38 mg中心点h/L的治疗浓度。CLT为3.05+/-0.56mL/min/kg，CL1为3.03+/-0.69mL/min/kg，差异无统计学意义(P=0.901)。建立了在试验剂量后2小时和6小时的抽样方案来预测AUC(T)(平均预测误差为1.64%，均方根误差为6.17%，绝对平均预测误差为4.94%)。此外，Bland-Altman图显示，两次抽样方案提供了可接受的准确的AUC(1)预测。采用两次抽样方案的测试剂量足以个性化造血细胞移植受者的初始白消安剂量。
This study aimed to predict the area under the curve (AUC) of the initial busulfan dose using a test dose with the sparse sampling scheme in adult patients who underwent hematopoietic cell transplant. A test dose of 0.8 mg/kg busulfan was used 2 days before twice-daily intravenous busulfan-based conditioning regimens were administered. The AUC and the clearance (CL) were calculated for both the test dose and the first dose (AUC(T), CLT, AUC(1,) and CL1) by noncompartmental analysis. The sparse sampling schemes of the test dose were developed by Bayesian method based on the population pharmacokinetic model. The optimal sparse sampling schemes were determined by evaluating the mean prediction error, the root mean square error, the absolute mean prediction error, and Bland-Altman plot. The mean AUC(1) was 7.20 +/- 1.48 mg center dot h/L, which ranged from 4.70 to 9.46 mg center dot h/L. The AUC(1) was below the therapeutic concentration of 7.38 mg center dot h/L in 45% (9 of 20) of the patients. The CLT of 3.05 +/- 0.56 mL/min/kg was not significantly different with the CL1 of 3.03 +/- 0.69 mL/min/kg (P = .901). A sampling scheme at 2 and 6 hours after the test dose was developed to predict the AUC(T) (mean prediction error of 1.64%, root mean square error of 6.17%, and absolute mean prediction error of 4.94%). Additionally, the Bland-Altman plot showed that the 2-sampling scheme provided an acceptably accurate prediction of the AUC(1). A test dose with a 2-sampling scheme was sufficient to personalize the initial busulfan dosing in hematopoietic cell transplant recipients.