Table 6. Administration of BU and Pharmacokinetic parameter estimation per Center (n=138).
| Centers | Busulfan Initial IV Dose | Busulfan, Dose adjusted | Method for estimating Busulfan concentration | Therapeutic Drug Target | The determination of pharmacokinetic parameters, estimated from the first dose. |
|---|---|---|---|---|---|
| CHU St-Justine, Canada | 0.8mg/kg/dose (infants≥3months and <1 year of age) 1 mg/kg/dose (children≥1 year and <4 years old) 0.8mg/kg/dose (children≥4 years old) | 5th dose | HPLC/LC-MS/MS | Css target = 600–900 ng/mL | Non-compartmental analysis (WinNonlin, version 3.1, Pharsight) |
| Geneva University Hospital, Switzerland | 0.8mg/kg/dose (infants≥3months and <1 year of age) 1 mg/kg/dose (children≥1 year and <4 years old) 0.8mg/kg/dose (children≥4 years old) | 4th dose | LC-MS/MS | Css target = 600–900 ng/mL | Non-compartmental analysis (WinNonlin, version 3.1, Pharsight) |
| Leiden University Medical Center Netherlands | 0.8 to 1mg/kg/dose (infants≥4 years of age); 1mg/kg/dose (infants<4 years old) |
5th or 9th dose | HPLC/LC-MS/MS | Css target = 740–910 ng/mL Then the dose was only adjusted by a maximum of 1 mg/kg every 6 hours. |
Non-compartmental analysis (WinNonlin, version 3.1, Pharsight) |
| Robert Debré University Hospital, France | <9kg (1mg/kg/dose) 9≥to<16kg (1.2mg/kg/dose) 16≥to≤23kg (1.1mg/kg/dose) >23to≤34kg (0.95mg/kg/dose) >34kg (0.8mg/kg/dose) | 7th or 9th dose | GC-MS | Css target = 600-1026 ng/mL | Non-compartmental analysis (WinNonlin, version 3.1, Pharsight) |
| SickKids Hospital, Canada | <9kg (1mg/kg/dose) 9 to <16kg (1.2mg/kg/dose) 16 to 23kg (1.1mg/kg/dose) 23 to 34kg (0.95mg/kg/dose) >34kg (0.8mg/kg/dose) |
3rd or 4th dose | GC-ECD | Css target = 889 ng/mL | Limited Sampling Strategy or Trapezoidal rule to calculate AUC |
Evaluation of Pharmacokinetic parameter estimations: A cross calibration study was conducted by our group with the collaboration of Pierre Fabre Laboratories between all centers participating in the study to validate analytical method used to determine the PK parameters from the first dose (data available upon request). Only centers with the measured BU concentrations falling within ± 20% of the therapeutic drug target concentrations were included for analysis of PK parameters. Abbreviations: AUC: Area under the curve; Css: Steady state concentration; GC-MS: Gas Chromatography Mass Spectrometry; GC-ECD: Gas Chromatography with Electron Capture Detector; HPLC: High Performance Liquid Chromatography; LC-MS/MS:Liquid chromatography–mass spectrometry