Pharmacokinetics and tolerability of intravenous busulfan in hematopoietic stem cell transplantation

Abstract

Intravenous (IV) busulfan has been developed to overcome variable absorption of oral busulfan and tested in several trials. We tested its pharmacological properties and tolerability in 16 Korean stem cell transplantation (SCT) patients. IV busulfan was administered at 0.8 mg/kg every six h for a total of 16 doses (days -7 to -4), which was followed by cyclophosphamide administration at 60 mg/kg every 24 h for two d (days -3 and -2). The median AUC(inf) values (at the first dose) and AUC(ss) (at the steady state) were 1060.4 microM.min (range: 511.1-1812.7) and 1092.5 microM.min (range: 539.7-1560.8) respectively. All patients had an AUC(inf) of <1500 microM.min at the first dose, and 13 of the 16 (81.3%) maintained AUC(ss) levels between 800 and 1500 microM.min. Thirteen of 16 patients showed successful engraftments but four patients (25%) developed hepatic VOD (two of which were fatal), three of whom had advanced disease at the time of SCT. Overall, pharmacokinetics of IV busulfan in our SCT patients appeared comparable with those observed in other study. However, hepatic VOD was a major morbidity in patients with advanced disease.

Busulfan dosing (Q6 or Q24) with adjusted or actual body weight, does it matter?

“…A review of the published literature reveals the utilization of either ABW or DBW for busulfan dosing calculations. 11–14,19 Modifications to these general guidelines have been to dose busulfan based on the lower of ABW or DBW 8,22 or to dose patients based on ABW only if they are within a certain percentage (20–25%) of their IBW. 9,15,16,21,23 Other reports have utilized DBW to dose IV busulfan for any weight above ideal.…”

Continuous infusion idarubicin and intravenous busulphan as conditioning regimen to autologous stem cell transplantation for patients with acute myeloid leukaemia

“…In both studies, no case of TRM was registered; however, most patients experienced severe mucositis, needing in the majority of cases TPN and narcotic analgesic agents. On the basis of a favourable toxicity profile of intravenous formulation of BU, described either in allogeneic or in autologous transplantation [5][6][7][8][9][10][11][12], we decided to modify our regimen by substituting the oral formulation of Bu with the intravenous one. As suggested for allogeneic transplants, a slight reduction of the total dose Bu from 16 mg/sqm to 12.8/sqm was adopted, without modifying the schedule of IDA.…”

“…Such a combination, commonly named BuCy, still represents the more frequent myeloablative conditioning regimen for AML in the allogeneic setting. Notwithstanding, oral Bu has a very narrow therapeutic index and acute toxicity may be related to absorption and disposition of the drug and metabolites [5][6][7][8]. In particular, precise delivery of the oral formulation is compromised by erratic gastrointestinal absorption, particularly in paediatric patients [5][6][7][8].…”

“…Notwithstanding, oral Bu has a very narrow therapeutic index and acute toxicity may be related to absorption and disposition of the drug and metabolites [5][6][7][8]. In particular, precise delivery of the oral formulation is compromised by erratic gastrointestinal absorption, particularly in paediatric patients [5][6][7][8]. In addition, difficulties in predicting and assessing dose delivered with oral administration of high-dose Bu result in a significant risk of lethal pulmonary or hepatic toxicity due to inadvertent overdosing; on the other hand, under dosing may potentially induce graft failure or recurrence of malignant disease after transplantation [9,10].…”

“…In addition, difficulties in predicting and assessing dose delivered with oral administration of high-dose Bu result in a significant risk of lethal pulmonary or hepatic toxicity due to inadvertent overdosing; on the other hand, under dosing may potentially induce graft failure or recurrence of malignant disease after transplantation [9,10]. Therefore, in the recent years different studies have suggested that the introduction of a parenteral formula of Bu, as part of a preparative regimen, can be more effective and can reduce morbidity and mortality associated with allo-SCT [5][6][7][8][9][10]. In contrast, very few studies have focused on the effectiveness and safety of intravenous (iv) Bu in autologous setting and most of these concern patients with non Hodgkin lymphoma in combination with cyclophosphamide and etoposide [11][12].…”