Pharmacokinetics of a test dose of intravenous busulfan guide dose modifications to achieve an optimal area under the curve of a single daily dose of intravenous busulfan in children undergoing a reduced-intensity conditioning regimen with hematopoietic stem cell transplantation.
We studied 30 pediatric patients with malignant (n = 16) or nonmalignant (n = 14) conditions. The preparative regimen consisted of fludarabine, intravenous (IV) busulfan (Bu) for 2 daily doses, and antithymocyte globulin before stem cell transplantation. A test dose of IV Bu (0.8 mg/kg), anticipated to target an area under the concentration-time curve (AUC) of 800 to 1200 micromol.min, was followed later by 2 daily doses adjusted according to the pharmacokinetics (PK) to target an AUC of 3200 to 4800 micromol.min. The median test dose AUC was 953 micromol.min (range, 439-1315 micromol.min). The median AUC of single daily doses was 3798 micromol.min (range, 1511-7254 micromol.min). PK-based dose modification was required in 20 patients: 12 were adjusted to a higher dose, and in 8 the dose was decreased. Nausea and vomiting were noted in 15 patients. No patient developed hepatic veno-occlusive disease or seizures. Full donor chimerism was attained in 20 patients (mean of 24.5 days), 3 achieved partial chimerism, 5 did not engraft, and in 2 it is too early to assess chimerism. Acute graft-versus-host disease developed in 11 patients, grades I to II developed in 10 patients, and grade III developed in 1. Four patients died of infection and 5 of progressive disease. Thus, PK of a test dose of IV Bu provided information to adjust subsequent daily doses of IV Bu: this resulted in a regimen that was feasible, safe, and convenient for administration to children.
Stem Cell Transplant Program, Children's Memorial Hospital, Feinberg School of Medicine, Department of Pediatrics, Northwestern University, Chicago, IL 60614, USA. mkletzel@northwestern.edu
Morris
M
Kletzel
David
D
Jacobsohn
Reggie
R
Duerst
D000293:Adolescent; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000401:mortality; D006801:Humans; D007223:Infant; D008297:Male; D019653:Myeloablative Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D009369:Neoplasms / Q000150:complications / Q000401:mortality / Q000628:therapy; D015996:Survival Rate; D018183:Transplantation Chimera; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods / Q000401:mortality; D014184:Transplantation, Homologous
D019653:Myeloablative Agonists; D002066:Busulfan