Yin J, Xiao Y, Zheng H, Zhang Y C
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Bone Marrow Transplant. 2015 May;50(5):696-705. doi: 10.1038/bmt.2015.14. Epub 2015 Mar 2.
I.v. 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 i.v. BU had the same clinical efficacy as i.v. BU administered four times daily. To observe the clinical efficacy and pharmacokinetics (PK) of once-daily i.v. BU and to evaluate the influence of glutathione S-transferase (GST) gene polymorphisms on once-daily i.v. BU PK in adult Chinese patients with allogeneic HSCT, we analyzed 25 patients receiving related or unrelated donor transplant conditioned with i.v. 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 i.v. BU were calculated as 4.02 mL/min per kg and 3380.77 μM/min, respectively. The estimated Cmax was 1.031±0.0325 μg/mL. The estimated t1/2 and Vd values were 3.618±0.1932 h and 1.212±0.0352 L/kg. The once-daily i.v. 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 Cmax (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 withA/*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.
静脉注射白消安（BU）已被证明具有更好的生物利用度，在造血干细胞移植（HSCT）前作为预处理方案的一部分使用时，其全身药物暴露可靠，血药水平更可预测，且毒性低于口服白消安。一些研究表明，每日一次静脉注射白消安与每日四次静脉注射白消安具有相同的临床疗效。为观察每日一次静脉注射白消安的临床疗效和药代动力学（PK），并评估谷胱甘肽S-转移酶（GST）基因多态性对成年中国异基因HSCT患者每日一次静脉注射白消安PK的影响，我们分析了25例接受基于静脉注射白消安方案预处理的相关或无关供体移植患者。中位随访32.7个月，所有患者的2年总生存率（OS）和无事件生存率（EFS）分别为64%和63.8%，所有患者的2年累积复发率为18.3%。基于高效液相色谱（HPLC）分析，静脉注射白消安的平均清除率和平均每日曲线下面积（AUC）分别计算为4.02 mL/min per kg和3380.77 μM/min。估计的Cmax为1.031±0.0325 μg/mL。估计的t1/2和Vd值分别为3.618±0.1932 h和1.212±0.0352 L/kg。每日一次静脉注射白消安的预处理方案耐受性良好，患者毒性较小，这很可能是因为PK可预测从而保证了剂量。我们的中国患者中没有GSTA1 *B/*B纯合子患者。观察到白消安代谢与GSTA1多态性之间存在显著关联。与GSTA1 *A/*A基因型组相比，GSTA1 *A/B基因型组的AUC显著更高（P<0.0001），Cmax更高（P=0.0003），清除率更低（P=0.0007）。与A/G基因型（P=0.0283）和G/*G基因型（P=0.0111）相比，GSTP1 *A/*A基因型的AUC更低。GSTP1 *A/A基因型的白消安清除率高于A/G基因型（P=0.0255）和G/*G基因型（P=0.0111）。此外，由于中国患者和白种人患者中GST基因多态性的分布频率不同，不同种族群体之间白消安的PK存在差异。
