Abstract 1179

Poster Board I-201

Introduction:

Intravenous (iv) busulfan can yield a more consistent dosing and pharmacokinetic profile than oral formulation, but there is still inter-patient variability in systemic exposure with iv busulfan. GST gene polymorphisms may explain the variability because busulfan is metabolized in liver through conjugation with GST family. Thus, we investigated the influence of polymorphisms of 3 GST genes, GSTA1, GSTM1, and GSTT1 on the clearance of iv busulfan in adult patients undergoing hematopoietic cell transplantation (HCT).

Patients and Methods:

We analyzed the PK data from 60 patients, who were included in a randomized trial of 4-times-daily (0.8 mg/kg q 6 h) versus once-daily (3.2 mg/kg once a day) iv busulfan in a conditioning therapy for HCT (Biol Blood Marrow Transplant 2007;13:1095). Limited sampling strategy was used for PK studies, which were performed for the first busulfan dosing using a validated LC with tandem MS. Busulfan plasma clearance (CL) was derived from 1 compartment model. GSTA1 was genotyped by PCR followed by RFLP, and GSTM1- and GSTT1-null genotypes were identified by PCR procedure.

Results:

GSTA1 genotyping revealed GSTA1*A/*A in 46 patients (77%) and GSTA1*A/*B in 14 (23%). GSTM1-null genotype was found in 25 patients (43%) and GSTT1-null genotype in 34 (59%). Each polymorphism of GST genes was not associated with sex or age of the patients. In univariate analysis, clearance (CL, mL/min/kg) of iv busulfan was significantly associated with GSTA1 polymorphisms (*A/*A vs. *A/*B, 2.036 ± 0.340 vs. 1.789 ± 0.295, P=0.017), but not with GSTM1 (present vs. null, 2.012 ± 0.390 vs. 1.915 ± 0.279, P=0.274) or GSTT1 (present vs. null, 2.047 ± 0.286 vs. 1.917 ± 0.380, P=0.064) polymorphisms. Actual body weight in kilogram was also significantly associated with CL of iv busulfan (Pearson's correlation coefficient, -0.420; P=0.001). Linear regression analysis demonstrated that GSTA1 gene polymorphism (regression coefficient, -0.255; 95% CI, -0.440 to -0.071; P=0.008) and actual body weight (regression coefficient, -0.012; 95% CI, -0.091 to -0.005; P=0.001) were independently significant factors for CL of iv busulfan. Null genotype of GSTM1 and/or GSTT1, although each polymorphism was not a significant factor, showed decreased clearance of iv busulfan both in patients with GSTA1 *A/*A and those with GSTA1 *A/*B (Figure 1). The CL was similar between in patients with GSTA1 *A/*A with null genotype of both GSTM1 and GSTT1 and in those with GSTA1 *A/*B with present genotype of both GSTM1 and GSTT1.

Figure 1
Figure 1. Clearance of intravenous busulfan according to GST gene polyphorphisms. Each bar denotes mean and 95% confidence interval for each group. A+M+T+ is for GSTA1 *A/*A and present genotype of both GSTM1 and GSTT1; A+(MorT)+ for GSTA1 *A/*A and present genotype of GSTM1 or GSTT1; A+M-T- for GSTA1 *A/*A and null genotype of both GSTM1 and GSTT1; A-M+T+ for GSTA1 *A/*B and present genotype of both GSTM1 and GSTT1; A-(MorT)+ for GSTA1 *A/*B and present genotype of GSTM1 or GSTT1; and A-M-T- for GSTA1 *A/*B and null genotype of both GSTM1 and GSTT1.
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Clearance of intravenous busulfan according to GST gene polyphorphisms. Each bar denotes mean and 95% confidence interval for each group. A+M+T+ is for GSTA1 *A/*A and present genotype of both GSTM1 and GSTT1; A+(MorT)+ for GSTA1 *A/*A and present genotype of GSTM1 or GSTT1; A+M-T- for GSTA1 *A/*A and null genotype of both GSTM1 and GSTT1; A-M+T+ for GSTA1 *A/*B and present genotype of both GSTM1 and GSTT1; A-(MorT)+ for GSTA1 *A/*B and present genotype of GSTM1 or GSTT1; and A-M-T- for GSTA1 *A/*B and null genotype of both GSTM1 and GSTT1.

Figure 1
Figure 1. Clearance of intravenous busulfan according to GST gene polyphorphisms. Each bar denotes mean and 95% confidence interval for each group. A+M+T+ is for GSTA1 *A/*A and present genotype of both GSTM1 and GSTT1; A+(MorT)+ for GSTA1 *A/*A and present genotype of GSTM1 or GSTT1; A+M-T- for GSTA1 *A/*A and null genotype of both GSTM1 and GSTT1; A-M+T+ for GSTA1 *A/*B and present genotype of both GSTM1 and GSTT1; A-(MorT)+ for GSTA1 *A/*B and present genotype of GSTM1 or GSTT1; and A-M-T- for GSTA1 *A/*B and null genotype of both GSTM1 and GSTT1.
View largeDownload slide

Clearance of intravenous busulfan according to GST gene polyphorphisms. Each bar denotes mean and 95% confidence interval for each group. A+M+T+ is for GSTA1 *A/*A and present genotype of both GSTM1 and GSTT1; A+(MorT)+ for GSTA1 *A/*A and present genotype of GSTM1 or GSTT1; A+M-T- for GSTA1 *A/*A and null genotype of both GSTM1 and GSTT1; A-M+T+ for GSTA1 *A/*B and present genotype of both GSTM1 and GSTT1; A-(MorT)+ for GSTA1 *A/*B and present genotype of GSTM1 or GSTT1; and A-M-T- for GSTA1 *A/*B and null genotype of both GSTM1 and GSTT1.

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Conclusion:

GSTA1 gene polymorphism was an important determining factor for the clearance of iv busulfan. Polymorphisms of GSTM1 and GSTT1 genes also appeared to have a supplementary role in the pharmacokinetics of iv busulfan.

Disclosures:

No relevant conflicts of interest to declare.

Topics:
busulfan, drug clearance, genes, glutathione s-transferase, hematopoietic stem cell transplantation, polymorphism, polymerase chain reaction, genotype determination, transplantation, linear regression

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2009 by The American Society of Hematology
2009
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