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.
Therapeutic drug monitoring, population pharmacokinetics models and external validation of high-dose methotrexate in pediatric acute lymphoblastic leukemia
Cangialosi, AlicePenultimo
;Di Paolo, AntonelloUltimo
2024-01-01
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
