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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., (© 2020 Wiley Periodicals LLC.)

Background: The prognosis of febrile neutropenia (FN) in childhood cancer has been considerably improved by the intensification of treatment, including systematic hospitalization and broad-spectrum antibiotics. As only few children present with a severe bacterial infection (SBI), clinical decision rules have been developed to distinguish those at risk for SBI. The aim of this study was to evaluate the reproducibility of six clinical decision rules proposed in the literature and to compare their performance., Methods: This retrospective two-center cohort study included all episodes of chemotherapy-induced FN in children admitted between January 2005 and December 2006. Each rule was applied to our patients. Their sensitivity (Se) and specificity (Sp) were calculated and compared with the authors' results, to assess reproducibility. The most predictive rule was defined in advance as that yielding 100% Se, the highest Sp, and the greatest simplicity for bedside application., Results: Three hundred seventy-seven episodes of FN in 167 patients were collected; 64 episodes were associated with SBI, including 36 with bacteremia. Four of the six rules were reproducible, but none were able to be validated. The most predictive rule for bacteremia had 96% Se (95% confidence interval (CI): 79-99%) and 25% Sp (95% CI: 19-33%), and the most predictive rule for SBI had 95% Se (95% CI: 87-98%), but no power of discrimination (Sp = 5%, 95% CI: 3-8%)., Conclusion: This study emphasizes the difficulty in identifying standardized decision rules in the management of a condition with numerous clinical variables like FN., (Copyright 2010 Wiley-Liss, Inc.)