Therapeutic drug monitoring, population pharmacokinetics models and external validation of high-dose methotrexate in pediatric acute lymphoblastic leukemia.

Introduction: High-dose MTX is used to treat pediatric acute lymphoblastic leukemia (ALL). The drug has a low therapeutic index and a highly interindividual variability in systemic exposure. These characteristics necessitate dose adjustments and therapeutic drug monitoring protocols, while population pharmacokinetic (POP/PK) models may enable more precise drug dosing. Therefore, we assessed the performance of external POP/PK models in ALL children receiving high-dose MTX.

Methods: We retrospectively harvested clinical and laboratory data from ALL children during their first two cycles of chemotherapy. A POP/PK model was elaborated using the Monolix suite 2024.R1. External models were selected from PUBMED based on strict inclusion/exclusion criteria, and their fit to the actual data was assessed by calculating bias (PE%) and precision (RMSE%).

Results: Thirty-seven ALL children participated in the study (18 males, median age 5.1 years, range 1.7-15.2 years), and six external POP/PK models were chosen. Except for one model (median PE% value, -97.45%), all models exhibited acceptable bias (median PE% values, -4.17% to 2.67%), despite none of them demonstrating good precision (median RMSE% values, 89.19% to 120.40%).

Conclusion: External models should be accurately evaluated before they are implemented in clinical practice, even when patients share very similar characteristics.