Precision Dosing Model Aims to Steady a Risky Transplant Drug in Children

Busulfan is one of the most consequential drugs given to children before an allogeneic hematopoietic stem cell transplant. A new prospective study from Children's Hospital of Fudan University in Shanghai set out to bring that dosing under tighter control, and its results underline just how often standard, one-size-fits-all regimens miss the mark in young patients. The research team enrolled 290 pediatric recipients of allogeneic stem cell transplants and collected 1,543 plasma busulfan concentration measurements between August 2020 and January 2026.

Drug levels were quantified with a validated HPLC-MS/MS assay, and the pharmacokinetic data were analyzed using nonlinear mixed-effects modeling, the standard statistical framework for population pharmacokinetics. The goal was to identify which patient characteristics drive variability in how quickly children clear the drug, and to build a model capable of predicting exposure for an individual child before the first dose is even given. The analysis showed that a two-compartment model with first-order elimination adequately described busulfan's behavior in these patients.

Body weight and age emerged as significant determinants of clearance, meaning that how fast a child eliminates the drug depends on both how big and how old they are. For a 70-kilogram reference individual, the population estimates of clearance and central volume of distribution were 12.4 liters per hour and 40.8 liters, respectively. External evaluation demonstrated that the model had good predictive performance when applied to data not used to build it, a critical test for any model intended for bedside use.

The clinical stakes of getting this right became clear when the researchers examined outcomes under conventional empirical dosing. Only about half of the patients — roughly 47.6 to 50.3 percent, depending on the analysis — achieved the target area under the concentration-time curve from zero to six hours (AUC0-6h) of 900 to 1,350 μM·min. The exposure-response analysis added a sobering dimension.

Using logistic regression, the team found that higher busulfan AUC0-6h was associated with mortality, with an odds ratio of approximately 1.002 per unit of exposure (95% CI 1.000–1.004), while no significant association was observed between exposure and acute graft-versus-host disease. Turning the model into something clinicians can actually use required two further steps. First, the team ran Monte Carlo simulations — thousands of virtual patient trials using the fitted model — to derive an initial dosing regimen stratified by both age and body weight.

Second, the researchers built a closed-loop model-informed precision dosing (MIPD) workflow: the initial dose is selected from the simulated regimen, therapeutic drug monitoring then measures actual busulfan concentrations, and a pharmacist-physician team adjusts the dose whenever the calculated AUC0-6h falls outside the prespecified target range. The closed-loop design matters because busulfan pharmacokinetics in children are notoriously unpredictable. By pairing a population model with real-time measurement and iterative adjustment, the workflow treats the first dose as a hypothesis to be tested rather than a final answer, bringing each patient's cumulative exposure toward the therapeutic window over the course of the conditioning regimen.

Still, the scale of the cohort — 290 children and more than 1,500 concentration measurements collected prospectively in a real-world clinical setting — gives the findings substantial weight.

Subject of Research: Population pharmacokinetics and model-informed precision dosing of busulfan in Chinese pediatric allogeneic hematopoietic stem cell transplantation

Article Title: Population pharmacokinetics and model-informed precision dosing of busulfan in Chinese pediatric allogeneic hematopoietic stem cell transplantation: a prospective real-world cohort study

Article References: Chen, Y., Jiang, W., Wang, P., Yu, L., Qian, X., Wang, G., Cai, J., Hu, M., Zhai, X., & Li, Z. (2026). Population pharmacokinetics and model-informed precision dosing of busulfan in Chinese pediatric allogeneic hematopoietic stem cell transplantation: a prospective real-world cohort study. Frontiers in Pharmacology, 17, Article 1974352. https://doi.org/10.3389/fphar.2026.1974352

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1974352

Keywords: busulfan, pediatric transplantation, hematopoietic stem cell transplantation, population pharmacokinetics, precision dosing, therapeutic drug monitoring, conditioning regimen, pharmacokinetic modeling, Monte Carlo simulation, narrow therapeutic index, allogeneic transplant, exposure-response