Assessment of Therapeutic Drug Monitoring and Generalizability of a Population PK Model for Busulfan Applied across Five Datasets

Busulfan is commonly used in hematopoietic stem cell transplantation conditioning, with therapeutic drug monitoring (TDM) guiding dose adjustments to promote target exposure attainment. Published busulfan population pharmacokinetic (popPK) models vary in structure and covariates, and it is unclear how broadly applicable one popPK model is across different datasets and patient populations. A popPK model was developed from a retrospective busulfan PK dataset (N = 109 patients). Individual PK parameters were derived by maximum a posteriori (MAP) estimation in four additional datasets. Model-based and TDM-based dosing performance was assessed and compared with noncompartmental analysis and standard weight-based dosing across the five datasets. The model was subsequently used to evaluate minimal sampling schemes. A two-compartment popPK model with sex and body surface area as covariates reliably estimated PK parameters and AUCs across five datasets (N = 464), closely agreeing with NCA. In the original dataset, weight-based dosing would have achieved target AUC in 34% of patients, compared with 40% and 80% using model-based and TDM-based dosing, respectively. Across remaining datasets, model-based dosing performed comparably to weight-based dosing. Sampling could be reduced to four time points, and even a single late sample enabled accurate AUC estimation. The single busulfan popPK model demonstrated adequate generalizability and performed equally with weight-based dosing for achieving specified AUCs. The model could also be used for AUC determination using minimal sampling, though its performance declined in datasets where sampling and dosing schemes differed from the original dataset, highlighting limitations in applying one popPK model across diverse scenarios.