Validation of pharmacokinetic model for quizartinib quantified by UPLC-MS/MS in patients with FLT3-ITD negative newly diagnosed acute myeloid leukemia

Autores de IIS La Fe

• Antonio Solana Altabella

  Autor

• María Choví Trull

  Autor

• Rebeca Rodríguez Veiga

  Autor

• Marina López Nogueroles

  Autor

• David Martínez Cuadrón

  Autor

• Mayte Gil Candel

  Autor

• Laura Torres Miñana

  Autor

• Evelyn Gloria Acuña Cruz

  Autor

• Isabel Cano Ferri

  Autor

• Blanca Boluda Pascual

  Autor

• Irene Navarro Vicente

  Autor

• María Del Pilar Lloret Madrid

  Autor

• Eva Barragán González

  Autor

• Jose Vicente Gil Orti

  Autor

• Mario Rodenas Rovira

  Autor

• Juan Eduardo Megías Vericat

  Autor

• José Luis Poveda Andrés

  Autor

• Pau Montesinos Fernández

  Autor

Participantes ajenos a IIS La Fe

• Iniesta-Navalón, C
• Labrador, J
• Peris-Ribera, JE

Grupos

• Grupo de Investigación de Farmacia

• Hematología y Hemoterapia

Abstract

PurposeQuizartinib pharmacokinetics in FLT3-ITD negative acute myeloid leukemia (AML) remain largely unexplored. This study aims to validate a population pharmacokinetics model (popPK) for quizartinib in plasma samples of FLT3-ITD negative AML patients. To do so, an ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated for the quantification of quizartinib.MethodsPlasma samples were collected from FLT3-ITD negative newly diagnosed AML patients undergoing quizartinib therapy at induction in the QUIWI phase II clinical trial [NCT04107727, PETHEMA group] between March 2020 and February 2022. The UPLC-MS/MS method was developed and validated. A previously described popPK model was validated using external validation techniques and implemented using the software NONMEM v7.5.ResultsThe developed UPLC-MS/MS method demonstrated high accuracy and precision with a linear range of 6 to 200 ng/mL, with relative standard deviation between 3-11 and accuracy of 88-97% from nominal values. The external validation of the quizartinib popPK model showed minimal bias at the population level (MdPE: -9.86%; ME: 0.50 ng/mL, p = 0.964), but moderate imprecision (MdAPE: 32.28%) and suboptimal accuracy (F20: 24.5%; F30: 43.4%). Individual predictions improved performance, with negligible bias (MdPE: -0.50%), acceptable precision (MdAPE: 11.27%), and F20 (64.2%) and F30 (77.4%) exceeding predefined thresholds. Visual predictive checks confirmed adequate prediction of median concentrations, though some deviations occurred at extremes.ConclusionThis study presents a replicable UPLC-MS/MS method for the determination of quizartinib in plasma. The validated popPK model can be used to optimize dosing strategies in future clinical studies.

© 2025. The Author(s).

Keywords

• Acute myeloid leukemia; Population pharmacokinetics; Quizartinib; Newly diagnosed; FLT3-ITD negative; UPLC-MS/MS