title: The importance of therapeutic drug monitoring (TDM) for parenteral busulfan dosing in conditioning regimen for hematopoietic stem cell transplantation (HSCT) in children.
abstract: BACKGROUND
  Series of observations indicate PK/PD variability challenging the accuracy of the body-weight based busulfan (Bu) dosing schedule for (HSCT) conditioning therapy. The purpose of this communication is to describe the frequency of dose changes in initially body-weight-based fixed IV Bu dose and to emphasize the importance of TDM.
  
  
  METHODS
  Sixty-two children (ages 2 months-18 years) were treated with IV busulfan doses based on body weight for myeloablation. TDM utilizing a limited sample strategy (trough concentration immediately before the 5th dose, followed by samples immediately after the end of the 2-h infusion peak, 4 h, and 6 h from initiation of the infusion) was performed in 46 of 62 subjects. Busulfan concentrations were determined by high-performance liquid chromatography (HPLC). AUC was calculated according to the trapezoidal rule.
  
  
  RESULTS
  We observed trough levels of 25-1244 µg/L, peak levels of 849-4586 µg/L, and AUC of 2225-12818 µg/L·h following body weight-based high-dose busulfan. The doses were changed in 54% of cases. AUC in 5 of 9 patients with VOD were within target, in 3 patients AUS was higher, and in 1 patient AUC was lower. One of the 2 patients with neurotoxicity had higher AUC. Engraftment was 100%, but relapse occurred in 25% of cases.
  
  
  CONCLUSIONS
  Our results demonstrate that even with IV busulfan, intra-individual PK/PD variability is challenging. Although AUC does not necessarily correspond with outcomes (due to the role of other factors the fact that doses were changed in 54% of cases underlines the importance of TDM.
authors.affiliation: Department of Medical Chemistry and Clinical Biochemistry, Division of Clinical Pharmacology, Faculty Hospital in Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Hundie
authors.initials: H
authors.lastname: Tesfaye
authors.affiliation: Department of Medical Chemistry and Clinical Biochemistry, Division of Clinical Pharmacology, Faculty Hospital in Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Romana
authors.initials: R
authors.lastname: Branova
authors.affiliation: Department of Medical Chemistry and Clinical Biochemistry, Division of Clinical Pharmacology, Faculty Hospital in Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Klapkova
authors.affiliation: Department of Medical Chemistry and Clinical Biochemistry, Division of Clinical Pharmacology, Faculty Hospital in Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Richard
authors.initials: R
authors.lastname: Prusa
authors.affiliation: Department of Paediatric Hematology and Oncology, Faculty Hospital in Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Daniela
authors.initials: D
authors.lastname: Janeckova
authors.affiliation: Department of Paediatric Haematology and Oncology, Faculty Hospital in Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic., Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Riha
authors.affiliation: Department of Paediatric Haematology and Oncology, Faculty Hospital in Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic., Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Sedlacek
authors.affiliation: Department of Paediatric Haematology and Oncology, Faculty Hospital in Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic., Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Keslova
authors.affiliation: Department of Paediatric Haematology and Oncology, Faculty Hospital in Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic., Prague, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Malis
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000293:Adolescent; D001835:Body Weight; D002066:Busulfan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004050:Ditiocarb / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D019653:Myeloablative Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*
chemical_list: D000276:Adjuvants, Immunologic; D019653:Myeloablative Agonists; D004050:Ditiocarb; D002066:Busulfan