title: Integration of modelling and simulation into the development of intravenous busulfan in paediatrics: an industrial experience.
abstract: Busulfan (Bu) is commonly used in preparative conditioning regimen prior to bone marrow transplantation in infants (< 1 year old), children and adolescents (up to 17 years old). The clinical development of an intravenous form of busulfan (Busilvex) was based on pharmacokinetic (PK) modeling and simulation techniques. A retrospective population PK analysis was initially performed from a first study in 24 pediatric patients (0.45-16.7 years old) and a log-linear relationship between body weight and Busilvex clearance was demonstrated with no age-dependency. For an optimal area under the curve (AUC) targeting, a new Bu dosing regimen [i.e. 5 dose levels (0.80 to 1.20 mg/kg) adjusted to 5 discrete weight categories] was developed and assessed through population PK-based simulations. The benefit from this new dosing strategy was validated in a second trial including 55 children (0.30-17.2 years old). This prospective trial confirmed the previous simulations: an efficient therapeutic targeting whatever the patient's age or body weight. Over 80% of the children were within the desired plasma exposure window, and the initial PK model was validated on the confirmatory dataset.
authors.affiliation: Institut de Recherche Pierre Fabre, Castres, France. laurent.nguyen@pierre-fabre.com
authors.forename: L
authors.initials: L
authors.lastname: Nguyen
mesh_terms: D000293:Adolescent; D000367:Age Factors; D001835:Body Weight; D002066:Busulfan / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004345:Drug Industry; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological; D019653:Myeloablative Agonists / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D010372:Pediatrics / Q000379:methods*; D011446:Prospective Studies; D015203:Reproducibility of Results; D012189:Retrospective Studies
chemical_list: D019653:Myeloablative Agonists; D002066:Busulfan