Weight-based strategy of dose administration in children using intravenous busulfan: clinical and pharmacokinetic results.
BACKGROUND
A prospective clinical trial was performed in order to validate the pharmacokinetic (PK) and clinical benefits of a new dosing schedule of intravenous busulfan (IV Bu) in children.


METHODS
IV Bu was administered as a 2-hr infusion every 6 hr for 4 days. Five dose levels were given according to body-weight strata.


RESULTS
The 67 children aged from 4 months to 17.2 years were followed up over 50 months after autologous or allogeneic stem-cell transplantation. Reduced PK variability was seen after IV Bu administration enabling efficient targeting with 78% of patients within the 900-1,500 µM · min therapeutic window and reproducible exposures across administrations. No neurological complications occurred. The low incidence of hepatic veno-occlusive disease (VOD) recorded was not correlated with high area under the curve (AUC). Only stomatitis was correlated with high AUC in the autologous group. The 4-year overall survival was 59% in the autologous group and 82% in the allogeneic group.


CONCLUSIONS
The new dosing schedule using IV Bu provides adequate therapeutic targeting from the first administration, with low toxicity and good disease control in high-risk children. The choice of this formulation of Bu should be considered because of its low morbidity and good outcome.
Pediatric Hematology, Hopital Enfants Timone, Marseille, France.
Gérard
G
Michel
Dominique
D
Valteau-Couanet
Jean-Claude
JC
Gentet
Hélène
H
Esperou
Gérard
G
Socié
Françoise
F
Méchinaud
François
F
Doz
Bénédicte
B
Neven
Yves
Y
Bertrand
Claire
C
Galambrun
François
F
Demeocq
Karima
K
Yakouben
Pierre
P
Bordigoni
Didier
D
Frappaz
Laurent
L
Nguyen
Gilles
G
Vassal
D000293:Adolescent; 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; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006504:Hepatic Veno-Occlusive Disease / Q000517:prevention & control; D006801:Humans; D007223:Infant; D007275:Injections, Intravenous; D008297:Male; D011379:Prognosis; D015996:Survival Rate; D014018:Tissue Distribution; D014184:Transplantation, Homologous
D018906:Antineoplastic Agents, Alkylating; D002066:Busulfan