1 Introduction Busulfan, a bifunctional DNA-alkylating agent, is widely applied as a chemotherapeutic in combination with cyclophosphamide, cytarabine, and fludarabine before allogeneic hematopoietic cell transplantation (HCT) ( The clinical application of busulfan is complicated by its high inter- and intra-individual pharmacokinetics/pharmacodynamics (PK/PD) variability, particularly in children ( Furthermore, owing to its narrow therapeutic index and large PK/PD variability, administering an initial busulfan IV dose based only on body weight (WT) may result in failure to reach the target therapeutic window ( Model-informed precision dosing utilizes population PK (popPK) models combined with maximum posterior Bayesian estimation to optimize both initial and subsequent dosing regimens based on TDM measurements ( GST alpha 1 ( GSTA1 ) genetic variations, and dosing schedule (day/time) are the most well-documented factors contributing to busulfan clearance variability ( Body size descriptors, including body surface area (BSA), fat-free mass (FFM), and normal fat mass (NFM), significantly influence busulfan PK in pediatric patients ( mat ), and distribution volume (V) based on FFM ( Time-varying CL was observed over a 4-day treatment with an every-6-h dosing regimen of busulfan ( Genetic polymorphisms in GSTA1 are associated with 8%27% reduction in CL ( Given this intricate interplay of physiological and pharmacological factors, comprehensive understanding of busulfan PK characteristics becomes essential for target exposure attainment
Aging alters the circadian system, particularly melatonin secretion, amplitude, and receptor sensitivity, and these changes affect sleep architecture, metabolism, and cognitive function
Results At concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in FRO cells, but not in ARO cells
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