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.
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 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.
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J
J
Yin
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Y
Y
Xiao
Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
H
H
Zheng
Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Y C
YC
Zhang
D000293:Adolescent; D000328:Adult; D064591:Allografts; D044466:Asian People; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics; D002681:China; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000097:blood / Q000235:genetics / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006720:Homozygote; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D019172:Transplantation Conditioning
C484555:GSTA1 protein, human; D005982:Glutathione Transferase; D002066:Busulfan