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New dosing nomogram and population pharmacokinetic model for young and very young children receiving busulfan for hematopoietic stem cell transplantation conditioning
Author(s) -
Poinsig Vianney,
Faivre Laura,
Nguyen Laurent,
Neven Benedicte,
Broutin Sophie,
Moshous Despina,
Bourget Philippe,
Dufour Christelle,
Dalle JeanHugues,
Galambrun Claire,
Devictor Benedicte,
Kemmel Veronique,
De Berranger Eva,
Gandemer Virginie,
Vannier Jean Pierre,
Jubert Charlotte,
Bondu Sabrina,
Mir Olivier,
Petain Aurelie,
Vassal Gilles,
Paci Angelo
Publication year - 2020
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.28603
Subject(s) - busulfan , dosing , medicine , nomogram , pharmacokinetics , population , transplantation , therapeutic drug monitoring , hematopoietic stem cell transplantation , cohort , area under the curve , oncology , environmental health
Background Busulfan (Bu) is the cornerstone of conditioning regimens prior to hematopoietic stem cell transplantation, widely used in both adults and children for the treatment of malignant and nonmalignant diseases. Despite an intravenous formulation, interindividual variability (IIV) remains high and optimal exposure difficult to achieve, especially in neonates and infants. Procedure To ensure both efficacy and safety, we set up in 2005 an observational study designed for children not fully assessed during the drug registration procedure. From a large cohort of 540 patients, we developed a Bu population pharmacokinetic model based on body weight (BW) and maturation concepts to reduce IIV and optimize exposure. A new dosing nomogram was evaluated to better fit the population pharmacokinetic model. Results Bu clearance IIV was significantly decreased from 61.3% (covariate‐free model) to 28.6% when combining BW and maturation function. Median Bu area under the curve (AUC) was 1179 µmol/L × min compared to 1025 with the EMA dosing nomogram for children <9 kg. The target AUC was reached for each BW strata, significantly increasing the percentages of patients achieving reaching the targeted AUC as compared to FDA schedule. Conclusion This new model made it possible to propose a novel dosing nomogram that better considered children below 16 kg of BW and allowed better initial exposure as compared to existing dosing schedules. This nomogram, which would be easy to use to determine an optimal dosing schedule in daily practice, will need to be validated in clinical routine. Therapeutic drug monitoring remains strongly advisable for small children and those with specific diseases.