Mariko Fukumoto, Takashi Sugiyama and Akira Ogamo
Original paper :AATEX 9(1):11-16
High dosage busulfan (1 mg/kg orally every 6 hours x16 doses) is an important component of many of the myeloablative protocols for hematopoietic stem cell transplantation (HSCT) in both adults and children. At an orally given dose, there is considerable variability in the systemic exposure of busulfan, typically expressed as the area under the drug concentration-time curve (AUC) or average concentration at steady state (Css = AUC/dose interval). Several investigators have identified relationships between busulfan AUC (or Css) and clinical outcome in patients undergoing HSCT. Generally, the risk of hepatic veno-occlusive disease of the liver (VOD), the severest toxicity of busulfan, is increased with busulfan AUC>5400ug h/L. In Europe and America, dose adjustment based on measured AUC is common.
However, analysis of cell killing action of busulfan has not yet been presented on a kinetic basis. In this report, we have attempted to make a more kinetically based analysis of the cell killing effect of busulfan, and to determine which type of cell killing action of busulfan shows. We assessed the busulfan concentration necessary for 90% cell kill (IC90) with various exposure times and the degradation rate constants under the culture conditions used. Busulfan was slowly eliminated during incubation, with a half-life of 19.3h and residual busulfan amounted to 40.75% of the initial level after a 24-h incubation at 37 oC. When IC90fs and exposure times were plotted on a log scale, a linear relationship with a slope of ?1 was seen for busulfan during shorter than 100 h. We analyzed cell kill kinetics of busulfan and showed the concentration-time product(C x T) dependence of cell killing action of the drug by colony-forming inhibition assays using Chinese hamster V79 cells. These results suggested that the AUC of busulfan is an important determinant of graft rejection and regimen-related toxicity in HSCT patients and indicated dose modification based on measured AUC is necessary for these patients in Japan.
Keywords: busulfan, Chinese hamster V79 cells, colony formation assay, cell cycle phase-nonspecific agents, AUC