title: New insights into the pharmacokinetics of intravenous busulfan in children with sickle cell anemia undergoing bone marrow transplantation.
abstract: BACKGROUND
  Busulfan (Bu) is an integral part of conditioning regimens for patients with sickle cell anemia (SCA) undergoing transplantation. Patients with SCA might predispose to transplant-related neurological and pulmonary toxicities due to pre-existing disease-related cerebrovascular and lung injury. Bu therapy appears to be an important contributing factor in this context.
  
  
  METHODS
  We studied the pharmacokinetics of intravenous Bu and clinical outcomes of 36 children with SCA undergoing bone marrow transplantation. Most patients had pre-existing organ system damage. Busulfan was administered every 6 hr for 4 days with pharmacokinetic-guided dose adjustment to target a conservative area under the concentration versus time curve (AUC) range of 900-1,350 µMol*min.
  
  
  RESULTS
  We found that the first-dose Bu clearance was significantly higher (P < 0.0005) than the subsequent daily clearance, which remained unchanged during the following days. After the first-dose, 69% of patients achieved the target range. We adapted a new dose-adjustment strategy targeting exposures to the lower end (900 µMol*min) of the AUC range after the first dose of Bu to avoid unnecessary dose increases on subsequent days due to differences in clearance. This strategy enabled most patients to maintain the AUC within therapeutic range following dose adjustments.
  
  
  CONCLUSIONS
  Differences in Bu clearance after the first-dose and subsequent daily doses in patients with SCA should be considered for pharmacokinetic-guided dose adjustment. Conservative AUC range and targeting exposures to the lower end of the range after the first dose was associated with negligible toxicity, and high engraftment and sickle cell-free survival rates.
authors.affiliation: International Center for Transplantation in Thalassemia and Sickle Cell Anemia, Mediterranean Institute of Hematology, Policlinico Tor Vergata, Rome, Italy.
authors.forename: Javid
authors.initials: J
authors.lastname: Gaziev
authors.forename: Antonella
authors.initials: A
authors.lastname: Isgrò
authors.forename: Alessia Francesca
authors.initials: AF
authors.lastname: Mozzi
authors.forename: Aurèlie
authors.initials: A
authors.lastname: Petain
authors.forename: Laurent
authors.initials: L
authors.lastname: Nguyen
authors.forename: Cristiano
authors.initials: C
authors.lastname: Ialongo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Dinallo
authors.forename: Pietro
authors.initials: P
authors.lastname: Sodani
authors.forename: Marco
authors.initials: M
authors.lastname: Marziali
authors.forename: Marco
authors.initials: M
authors.lastname: Andreani
authors.forename: Manuela
authors.initials: M
authors.lastname: Testi
authors.forename: Katia
authors.initials: K
authors.lastname: Paciaroni
authors.forename: Cristiano
authors.initials: C
authors.lastname: Gallucci
authors.forename: Gioia
authors.initials: G
authors.lastname: De Angelis
authors.forename: Cecilia
authors.initials: C
authors.lastname: Alfieri
authors.forename: Michela
authors.initials: M
authors.lastname: Ribersani
authors.forename: Guido
authors.initials: G
authors.lastname: Lucarelli
mesh_terms: D000293:Adolescent; D064591:Allografts; D000755:Anemia, Sickle Cell / Q000401:mortality / Q000628:therapy*; D016026:Bone Marrow Transplantation; D002066:Busulfan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D019653:Myeloablative Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011446:Prospective Studies; D015996:Survival Rate; D013997:Time Factors; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D019653:Myeloablative Agonists; D002066:Busulfan
keywords: bone marrow transplantation; children; clearance; intravenous busulfan; pharmacokinetics; sickle cell anemia