Mini test dose of intravenous busulfan (Busulfex?) in allogeneic non-myeloablative stem cell transplantation, followed by liquid chromatography tandem-mass spectrometry

摘要

Busulfan (Bu) has been used for almost three decades in the conditioning of hematopoietic stem cell transplant. Bu has a very diverse gastrointestinal absorption, which in association with its emetic effect in high doses makes inter- and intra-individual oral bioavailability and thus systemic exposure very variable and difficult to predict (1, 2, 3). If the systemic exposure is below the therapeutic window there is an increased risk of lack of engraftment (4) and, in chronic myel-ogenous leukemia (CML) patients, disease relapse (5), while overexposure results in an increased incidence of high-dose related toxicities like hepatic veno-occlusive disease (6, 7). It is important to note that "busulfan concentration-response relationships are regimen-, age- and disease-dependent" as emphasized by McCune et al. (8). Therapeutic dose monitoring (TDM) gained an important role in the setting of oral Bu dose as it became clear that the level of systemic exposure influenced the toxicity, engraftment, and relapse rates. To give an idea of the importance of TDM, a test dose prior to starting the conditioning regimen with home-administered oral Bu in 153 patients evidenced that as many as 68% of them would have drug exposures out of the therapeutic window (900-1,500 muM?min) with the standard dose of 1 mg/kg of ideal body weight every 6 hr (9).