New dosing nomogram and population pharmacokinetic model for young and very young children receiving busulfan for hematopoietic stem cell transplantation conditioning

Abstract

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.

Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study

“…Bu, taking into consideration the genetic marker for GSTA1 metabolic capacity. Previous large multicentric PopPK studies were performed in mixed pediatric populations 16,17,21,33 . The McCune et al 16 model also included adult patients and can therefore be applied in a wider population.…”

“…Previous large multicentric PopPK studies were performed in mixed pediatric populations. 16 , 17 , 21 , 33 The McCune et al 16 model also included adult patients and can therefore be applied in a wider population. However, these studies did not account for markers for GSTA1 metabolic capacity, which were reported in several studies to significantly influence Bu PK.…”

“…The analysis was also extended to dosing nomograms not enabling to calculate CL 6,14,21 . Each model's ability to predict first doses resulting in AUCs within the therapeutic window was assessed.…”

“…The analysis was also extended to dosing nomograms not enabling to calculate CL. 6 , 14 , 21 Each model's ability to predict first doses resulting in AUCs within the therapeutic window was assessed. The model‐predicted dose (Dose model ) calculations using each model are shown in Supplemental Material S9 , with the AUCs predicted by each model (AUC model ) calculated using Equation ( 6 ): …”

“…The analysis was also extended to dosing nomograms not enabling to calculate CL. 6,14,21 Bu exposure was expressed as AUC in mg•h/L, in keeping with international attempts to harmonize the expression of Bu plasma exposure. 37 The first-dose target AUC was set to 19.7 mg•h/L (4800 µM•min), and the therapeutic window was set to 14.8-24.6 mg•h/L (3600-6000 µM•min) for q24h dosing.…”