Novel pharmacokinetic behavior of intravenous busulfan in children with thalassemia undergoing hematopoietic stem cell transplantation: a prospective evaluation of pharmacokinetic and pharmacodynamic profile with therapeutic drug monitoring

Abstract

We prospectively studied the pharmacokinetics (PK) and clinical outcomes of intravenous busulfan (Bu) in 71 children with preexisting liver damage who underwent hematopoietic stem cell transplantation for thalassemia. Intravenous Bu was administered every 6 hours as part of a conditioning regimen with PK-based dose adjustment to target a conservative area under the concentration-versus-time curve (AUC) range (900-1350 Mol*min). The first-dose Bu clearance (CL) was significantly higher than the subsequent daily CL that remained unchanged in the ensuing days. One-third of patients required dose escalation based on dose 1 AUC, whereas dose reduction was needed in the subsequent days. At doses 5, 9, and 13, 78%, 81%, and 87% of patients, respectively, achieved the target range of AUC. A population PK analysis confirmed that the first-dose CL was 20% higher and that body weight was the most important covariate to explain PK variability. Patients with variant GSTA1*B had a 10% lower Bu CL than wild-type. These results suggest that the disease-specific behavior of intravenous Bu PK should be considered for PK-guided dose adjustment in patients with thalassemia, and the use of a conservative AUC range resulted in low toxicity, good engraftment, and good survival rate. (Blood. 2010;115(22):4597-4604)

Conditioning regimens in allo-SCT for thalassemia major

“…I.v. BU along with therapeutic dose monitoring and dose modifications was a promising strategy to reduce RRT and potentially reduce the risk of graft rejection as illustrated in the study by Gaziev et al 17 However, as demonstrated in the study by Chiesa et al 10 although this approach was effective in reducing RRT, it was not able to reduce the risk of graft rejection in patients with very high-risk thalassemia major. More recently, Anurathapan et al reported a novel approach of administration of one or two courses of immune-suppressive therapy with a combination of fludarabine and dexamethsaone one to two months before the start of conditioning and followed this up with a reduced-toxicity myeloablative conditioning regimen consisting of fludarabine, i.v.…”

Glutathione S-transferase gene variations influence BU pharmacokinetics and outcome of hematopoietic SCT in pediatric patients

“…Although some studies have shown that GSTA1 genotypes influence the PK of oral and i.v. BU in both adults and children; 17,[26][27][28][29][30] others did not find this association. 15,31,32 In a small pilot study, we have shown that polymorphisms in GSTM1 might influence the PK of BU.…”

“…BU CL in individuals with combined GSTM1 and GSTT1 null genotypes, but not in individuals with GSTM1 null genotype alone, 39 whereas others reported absence of such association. 17,26,27,[30][31][32] The compensatory action of other GST isoforms to defective enzyme activity has been also demonstrated. 39 We did not find clear combined effect or interaction between GSTM1 and GSTA1 genotypes.…”

“…15,17,26,30,32 GST genetic variants and clinical outcomes of HSCT Better EFS was seen in homozygous GSTA1*A2 patients, which is likely due to a significantly lower BU levels seen in these individuals. Indeed, lower Css correlated with better EFS, which is in accordance with our observation 38 and with previous reports.…”

“…Our observation is in accordance with the functional studies suggesting higher GSTA activity in GSTA1*A carriers 10,22,24 and is also supported by several previous reports. 17,[26][27][28][29][30] Decreased CL following oral BU was seen in adults and children with GSTA*B haplotype; 17,29,31 a significant decrease in CL following i.v. BU was observed in pediatric GSTA1*B patients; 21,22 and accordingly increased BU CL correlated with GSTA1*A haplotype.…”