GRAFT-REJECTION AND TOXICITY FOLLOWING BONE-MARROW TRANSPLANTATION INRELATION TO BUSULFAN PHARMACOKINETICS

We have determined the relationships between busulfan average concentr ation at steady-state and (1) rejection of graft, and (2) regimen-rela ted toxicity, and have evaluated the dependence of busulfan clearance/ F on body size and age. Patients received 16-30 mg/kg of busulfan foll owed by cyclophosphamide in doses of 120, 150, 174, or 200 mg/kg or 8 g/m(2) in preparation for autologous, syngeneic or allogeneic grafts v arying in compatibility from HLA-matched siblings to HLA-partially-mat ched unrelated donors. In a multivariate Cox time-to-rejection analysi s, only busulfan concentration remained a significant determinant of r ejection, P = 0.0154. An average concentration of busulfan at steady-s tate of at least 200 ng/ml was needed to avoid rejection of a matched- sibling graft, while 600 ng/ml was needed to avoid rejection of HLA-pa rtially-matched related or HLA-matched unrelated donor grafts. The tox icity of the cytoreductive regimen correlated with busulfan average co ncentration at steady-state (r(s) = 0.717). Busulfan clearance/F expre ssed relative to body weight, ideal body weight or surface area declin ed with age during the first decade of life. Over the entire span of a ge, the coefficient of variation in clearance/F for all ages was simil ar when clearance/F was expressed in absolute terms (ml/min) and when adjusted for body surface area; the coefficient of variation was great er for clearance/F when expressed relative to total or ideal body weig ht. We conclude that busulfan concentration in plasma is an important determinant of graft survival and regimen-related toxicity, and that t he variability of busulfan pharmacokinetics with age precludes the use of a fixed dose for all ages and indications.