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Article

External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia

1
Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
2
Postdoctoral Research Station of Clinical Medicine and Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha 410013, China
3
Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha 410013, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work and shared the first authorship.
Pharmaceutics 2023, 15(2), 569; https://doi.org/10.3390/pharmaceutics15020569
Submission received: 30 December 2022 / Revised: 5 February 2023 / Accepted: 7 February 2023 / Published: 8 February 2023

Abstract

Background: Methotrexate (MTX) is a key immunosuppressant for children with acute lymphoid leukemia (ALL), and it has a narrow therapeutic window and relatively high pharmacokinetic variability. Several population pharmacokinetic (PopPK) models of MTX in ALL children have been reported, but the validity of these models for model-informed precision dosing in clinical practice is unclear. This study set out to evaluate the predictive performance of published pediatric PopPK models of MTX using an independent patient cohort. Methods: A PubMed literature search was performed to identify suitable models for evaluation. Demographics and measurements of the validation dataset were retrospectively collected from the medical records of ALL children who had received intravenous MTX. Predictive performance for each model was assessed by visual comparison of predictions to observations, median and mean predicted error (PE), and relative root mean squared error (RMSE). Results: Six models were identified for external evaluation, carried out on a dataset containing 354 concentrations from 51 pediatrics. Model performance varied considerably from one model to another. Different models had the median PE for population and individual predictions at −33.23% to 442.04% and −25.20% to 6.52%, mean PE for population and individual predictions at −25.51% to 780.87% and 1.33% to 64.44%, and RMSE for population and individual predictions at 62.88% to 1182.24% and 63.39% to 152.25%. All models showed relatively high RMSE. Conclusions: Some of the published models showed reasonably low levels of bias but had some problems with imprecision, and extensive evaluation is needed before model application in clinical practice.
Keywords: methotrexate; children; acute lymphoid leukemia; population pharmacokinetics; external validation methotrexate; children; acute lymphoid leukemia; population pharmacokinetics; external validation

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MDPI and ACS Style

Wang, S.; Yin, Q.; Yang, M.; Cheng, Z.; Xie, F. External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia. Pharmaceutics 2023, 15, 569. https://doi.org/10.3390/pharmaceutics15020569

AMA Style

Wang S, Yin Q, Yang M, Cheng Z, Xie F. External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia. Pharmaceutics. 2023; 15(2):569. https://doi.org/10.3390/pharmaceutics15020569

Chicago/Turabian Style

Wang, Shengfeng, Qiufen Yin, Minghua Yang, Zeneng Cheng, and Feifan Xie. 2023. "External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia" Pharmaceutics 15, no. 2: 569. https://doi.org/10.3390/pharmaceutics15020569

APA Style

Wang, S., Yin, Q., Yang, M., Cheng, Z., & Xie, F. (2023). External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia. Pharmaceutics, 15(2), 569. https://doi.org/10.3390/pharmaceutics15020569

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