Once-daily i.v. BU-based conditioning regimen before allogeneic hematopoietic SCT: a study of influence of GST gene polymorphisms on BU pharmacokinetics and clinical outcomes in Chinese patients
Once-daily i.v. BU-based conditioning regimen before allogeneic hematopoietic SCT: a study of influence of GST gene polymorphisms on BU pharmacokinetics and clinical outcomes in Chinese patients
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DOI：
10.1038/bmt.2015.14
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发表时间：
2015-05
影响因子：
4.8
通讯作者：
Jin Yin;Yi Xiao;H. Zheng;Yao Zhang
中科院分区：
文献类型：
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作者：
Jin Yin;Yi Xiao;H. Zheng;Yao Zhang
在造血干细胞移植（HSCT）前，与口服BU相比，静脉BU已被证明具有更好的生物利用度、可靠的全身药物暴露、更可预测的血液水平和更低的毒性。一些研究表明，每天一次静脉注射布鲁里菌与每天四次静脉注射布鲁里菌具有相同的临床疗效。为了观察每日一次静脉注射BU的临床疗效和药代动力学（PK），并评估谷胱甘肽s -转移酶（GST）基因多态性对中国成年同种异体造血干细胞移植患者每日一次静脉注射BU PK的影响，我们分析了25例接受相关或非相关供体移植的以静脉注射BU为基础的方案的患者。中位随访32.7个月，所有患者的2年OS和EFS分别为64%和63.8%，所有患者的2年累积复发率为18.3%。通过高效液相色谱法计算出iv BU的平均清除率为4.02 mL/min / kg，平均日曲线下面积（AUC）为330.77 μ M/min。cmax为1.031±0.0325 μg/mL。估计t1 /2和V d值分别为3.618±0.1932 h和1.212±0.0352 L/kg。每天一次的静脉注射以乙肝为基础的调理方案对患者的耐受性非常好，毒性很小，很可能是因为剂量保证和可预测的PK。我们的中国患者中没有GSTA1* B/* B纯合子患者。研究发现，BU代谢与GSTA1多态性之间存在显著关联。GSTA1* A/* B基因型组的AUC （P< 0.0001）、cmax （P= 0.0003）和清除率（P= 0.0007）均显著高于GSTA1* A/* A基因型组。GSTP1* A/* A基因型的AUC低于* A/* G （P= 0.0283）和* G/* G基因型（P= 0.0111）。GSTP1* A/* A基因型的BU清除率高于* A/* G基因型（P= 0.0255）和* G/* G基因型（P= 0.0111）。此外，由于GST基因多态性在中国患者和高加索患者中的分布频率不同，不同民族之间的BU中PK存在差异。
Iv BU has been proven to have better bioavailability, reliable systemic drug exposure with more predictable blood levels and lower toxicity than oral BU when used as part of conditioning regimens before hematopoietic SCT (HSCT). Some studies have shown that once-daily iv BU had the same clinical efficacy as iv BU administered four times daily. To observe the clinical efficacy and pharmacokinetics (PK) of once-daily iv BU and to evaluate the influence of glutathione S-transferase (GST) gene polymorphisms on once-daily iv BU PK in adult Chinese patients with allogeneic HSCT, we analyzed 25 patients receiving related or unrelated donor transplant conditioned with iv BU-based regimens. With a median follow-up of 32.7 months, the 2-year OS and EFS were 64 and 63.8% for all the patients, respectively, and the 2-year cumulative incidence of relapse for all patients was 18.3%. On the basis of HPLC analysis, the mean clearance and mean daily area under the curve (AUC) of iv BU were calculated as 4.02 mL/min per kg and 3380.77 μ M/min, respectively. The estimated C max was 1.031±0.0325 μg/mL. The estimated t 1/2 and V d values were 3.618±0.1932 h and 1.212±0.0352 L/kg. The once-daily iv BU-based conditioning regimen was very well tolerated with minor toxicity in patients, most likely because of dose assurance with predictable PK. There was no GSTA1* B/* B homozygous patient in our Chinese patients. A significant association between BU metabolism and GSTA1 polymorphism was observed. The GSTA1* A/* B genotype group showed a significantly higher AUC (P< 0.0001), higher C max (P= 0.0003) and lower clearance (P= 0.0007) than the GSTA1* A/* A genotype group. AUC was lower in GSTP1* A/* A genotypes compared with* A/* G (P= 0.0283) and* G/* G genotypes (P= 0.0111). The BU clearance in GSTP1* A/* A genotype was shown to be higher than* A/* G (P= 0.0255) and* G/* G genotypes (P= 0.0111). In addition, the differences of PK in BU among different ethnic groups existed because of the different distribution frequencies of GST gene polymorphism in Chinese patients and Caucasian patients.