title: Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring.
abstract: BACKGROUND
  Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability.
  
  
  OBJECTIVE
  A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated.
  
  
  METHODS
  Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16-23 kg; 0.95 mg/kg for >23-34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3-17.2 years (median 5.6 years).
  
  
  RESULTS
  No difference in AUC values was observed between weight strata (mean +/- SD 1248 +/- 205 micromol.min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900-1500 micromol.min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.
authors: Institut Gustave Roussy, Villejuif, France.
authors: G
authors: G
authors: Vassal
authors: G
authors: G
authors: Michel
authors: H
authors: H
authors: Espérou
authors: J C
authors: JC
authors: Gentet
authors: D
authors: D
authors: Valteau-Couanet
authors: F
authors: F
authors: Doz
authors: F
authors: F
authors: Mechinaud
authors: C
authors: C
authors: Galambrun
authors: B
authors: B
authors: Neven
authors: H
authors: H
authors: Zouabi
authors: L
authors: L
authors: Nguyen
authors: C
authors: C
authors: Puozzo
mesh_terms: D000293:Adolescent; D000367:Age Factors; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001835:Body Weight; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006402:Hematologic Diseases / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D008558:Melphalan / Q000627:therapeutic use; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D033581:Stem Cell Transplantation
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D002066:Busulfan; D008558:Melphalan