Busulfan disposition and hepatic veno-occlusive disease in children undergoing bone marrow transplantation

Abstract

Hepatic veno-occlusive disease (HVOD) is a frequent life-threatening toxicity in patients undergoing bone marrow transplantation (BMT) after the administration of a high-dose busulfan-containing regimen. Recent studies have shown that the morbidity and mortality of HVOD may be reduced in adults by pharmacologically guided dose adjustment of busulfan. We analyzed the pharmacodynamic relationship between busulfan disposition and HVOD in 61 children (median age, 5.9 years) with malignant disease. Busulfan, given at a dose ranging from 16 mg/kg to 600 mg/m2, was combined with one or two other alkylating agents (cyclophosphamide, melphalan, thiotepa). Only 3 patients received the standard busulfan/cyclophosphamide (BUCY) regimen. A total of 24 patients (40%) developed HVOD, which resolved in all cases. A pharmacokinetics study confirmed the previously reported wide interpatient variability in busulfan disposition but did not reveal any significant alteration in children with HVOD. The mean area under the concentration-time curve (AUC) after the first dose of busulfan was higher in patients with HVOD (6,811 +/- 2,943 ng h ml-1) than in patients without HVOD (5,760 +/- 1,891 ng h ml-1., P = 0.10). This difference reflects the higher dose of busulfan given to patients with HVOD. No toxic level could be defined and, moreover, none of the toxic levels identified in adults were relevant. The high incidence of HVOD in children given 600 mg/m2 busulfan may be linked to the use of more intensive than usual high-dose chemotherapy regimens and/or drug interactions. Before the prospective evaluation of busulfan dose adjustment in children, further studies are required to demonstrate firmly the existence of a pharmacodynamic relationship in terms of toxicity and allogeneic engraftment, especially when busulfan is combined with cyclophosphamide. The maximal tolerated and minimal effective AUCs in children undergoing BMT are likely to depend mainly upon the disease, the nature of the combined high-dose regimen, and the type of bone marrow transplant.

Influence of GST gene polymorphisms on busulfan pharmacokinetics in children

“…This finding accords with studies that suggest a relation between VOD and a higher BU exposure. [2][3][4] However, they reported lower drug levels and higher clearance in GSTM1-null individuals, suggesting that VOD may be mediated by glutathione depletion, possibly through higher GSTA1 activity. The study of Bredschneider et al 19 contrasts with this explanation by showing that neither GSTA1 protein expression nor conjugation activity was affected by GSTM1 status in human liver tissue.…”

“…It seems that many factors are equally important for VOD development, including underlying disease, pre-existing risk for VOD and particularly other drugs administered concomitantly with BU. 2,18,36 Recently, a higher incidence of acute GVHD (grade X2) was seen in patients with greater BU exposure. 18 In our study group, there were only two such patients; both had GSTM1 null genotype and no correlation was seen with BU exposure (P ¼ 0.9).…”

“…High drug exposure leads to increased risk of veno-occlusive disease (VOD), whereas low drug exposure has been associated with a higher risk of disease recurrence and graft failure. [1][2][3][4] Accordingly, steady-state BU plasma concentration and area under the concentration-time curve (AUC) correlate with the incidence of these clinical events. [1][2][3][4] Intravenous (IV) administration has consequently gained popularity, especially in children, as IV pharmacokinetics can be more predictive than pharmacokinetics after oral administration.…”

“…[1][2][3][4] Accordingly, steady-state BU plasma concentration and area under the concentration-time curve (AUC) correlate with the incidence of these clinical events. [1][2][3][4] Intravenous (IV) administration has consequently gained popularity, especially in children, as IV pharmacokinetics can be more predictive than pharmacokinetics after oral administration. [5][6][7] Nevertheless, important interindividual variability still persists 8 and several additional factors contribute to such observations.…”

Age-dependent pharmacokinetic profile of single daily dose i.v. busulfan in children undergoing reduced-intensity conditioning stem cell transplant

“…7 BU was previously available for only oral administration, and erratic absorption of the drug contributed to unpredictable blood levels and variable therapeutic and side effects. [8][9][10] The availability of an i.v. formulation of BU has removed some uncertainties associated with its adsorption, but variability in its pharmacokinetic (PK) profile remains significant.…”