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Integration of modelling and simulation into the development of intravenous busulfan in paediatrics: an industrial experience
Author(s) -
Nguyen L.
Publication year - 2008
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2008.00651.x
Subject(s) - busulfan , medicine , dosing , regimen , body surface area , population , pediatrics , pharmacokinetics , body weight , clinical trial , transplantation , hematopoietic stem cell transplantation , environmental health
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.