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Pharmacokinetic Behavior and Appraisal of Intravenous Busulfan Dosing in Infants and Older Children: The Results of a Population Pharmacokinetic Study From a Large Pediatric Cohort Undergoing Hematopoietic Stem-Cell Transplantation

Paci, Angelo PharmD, PhD*; Vassal, Gilles MD, PhD*; Moshous, Despina MD, PhD; Dalle, Jean-Hugues MD, PhD; Bleyzac, Nathalie PharmD, PhD§; Neven, Bénédicte MD, PhD; Galambrun, Claire MD, PhD; Kemmel, Véronique PharmD, PhD; Abdi, Zeinab D. PharmD**; Broutin, Sophie PharmD*; Pétain, Aurélie PharmD**; Nguyen, Laurent PharmD, PhD**

doi: 10.1097/FTD.0b013e31824c2f60
Original Article

Background Intravenous (IV) busulfan (Bu) dosing approved in Europe based on 5 body weight (BW) strata has been validated for targeting Bu exposures in children undergoing hematopoietic stem-cell transplantation and with mostly malignant diseases. The authors conducted an observational study aiming to investigate the behavior and ontogeny of IV Bu pharmacokinetic (PK) disposition, and to reevaluate the consistency of the BW-based dosing in very young children with rare diseases.

Methods The observational study comprised 115 patients, mostly infants with immunodeficiencies and metabolic inherited disorders and with altered liver function and/or iron overload. Additional data (90 children, mostly malignant diseases) were pooled with the first data set. The overall data (205 children aged from 10 days to 15 years) were analyzed using population PK modeling.

Results The BW remained the main determinant of IV Bu PK, and no further covariate effect was identified. Bu clearance (CL) variability was best described by BW allometric functions. Increase of drug CL with the child's growth was faster in younger children. This pattern is likely related to the maturation of GSTA1 enzymes during infancy and was accounted for in the model by estimating a higher BW allometric exponent in children <9 kg compared with that in children ≥9 kg. IV Bu PK was not modified in children with altered liver function and/or iron overload, and no disease specific difference was observed. Bu dosing either adjusted according to the final model or with the approved EU labeling yields similar targeting performances. For both dosing strategies, the percent of patients achieving the therapeutic area under the curve window (900–1500 μmole·min/L were 60% and 70%–90% in children <9 and ≥9 kg, respectively.

Conclusions A population PK model accounting for the highest Bu CL in the youngest patients was validated on training and evaluation data sets. The BW-based dosing strategy recommended in Europe proved to be consistent on a large paediatric cohort representative of the population heterogeneity observed in hematopoietic stem-cell transplantation.

*Institut Gustave Roussy, Villejuif

Hôpital Necker-Enfants Malades, Paris

Hôpital Robert Debré, Paris

§Hospices Civils, Lyon

AP-HM La Timone, Marseille

CHU Strasbourg, Strasbourg

**Institut de Recherche Pierre Fabre, Boulogne, France.

A. Paci and G. Vassal equally contributed to this work.

The authors declare no conflicts of interest.

Correspondence: Laurent Nguyen, PharmD, PhD, Département Pharmacocinétique Oncologie, Institut de Recherche Pierre Fabre, Centre de Recherche et Développement, 3 Avenue Hubert Curien, BP 13562, 31035 Toulouse Cedex 01, France (e-mail:

Received September 19, 2011

Accepted January 20, 2012

© 2012 Lippincott Williams & Wilkins, Inc.