Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation.
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 2 months to 59 yr (mean 10, median 12 yr) and had the following diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4 mg/kg (mean +/- SD, 1.21 +/- 0.41, 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.
Bostrom
Bruce
B
Pediatric Oncology, Children's Hospitals and Clinics, 2525 Chicago Avenue South, #32-4150, Minneapolis, MN 55404, USA. bostrom@childrenshc.org
Enockson
Karen
K
Johnson
Amy
A
Bruns
Alyssa
A
Blazar
Bruce
B
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D016026:Bone Marrow Transplantation / Q000276:immunology; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D006207:Half-Life; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000601:surgery; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000601:surgery*; D008661:Metabolism, Inborn Errors / Q000601:surgery; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000601:surgery; D012044:Regression Analysis; D013789:Thalassemia / Q000601:surgery*; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D002066:Busulfan