Amy Johnson

Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation

Abstract: We have analyzed the plasma pharmacokinetics of busulfan in 272 patients receiving high‐dose oral busulfan and intravenous cyclophosphamide in conjunction with allogeneic or autologous bone marrow transplantation. The patients ranged in age from 2u2003months to 59u2003yr (mean 10, median 12u2003yr) and had the following diagnoses: thalassemia or sickle cell anemia (nu2003=u200374); leukemia or myelodysplasia (nu2003=u2003112); inborn errors of metabolism (nu2003=u200341) or immunodeficiency (nu2003=u200345). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4u2003mg/kg (mean ± SD, 1.21u2003±u20030.41, median 1.15). Busulfan was quantitated using ultraviolet absorbance detection after derivatization and HPLC separation. Pharmacokinetic parameters were derived by modeling the raw data to fit first‐order single compartment kinetics. The kinetic parameters showed wide interpatient variability independent of age and diagnosis. There was a statistically significant correlation of age with the following parameters: area under the curve (AUC); maximal concentration; minimum concentration; clearance; volume of distribution and absorption half‐time. The coefficients of determination (i.e. correlation coefficient squared) were low ranging from 0.04 to 0.12 implying only a small part (i.e. 4–12%) of the variance was explained by age. Although busulfan pharmacokinetics are age‐related most of the variability is not explained by age or diagnosis.