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Purpose <p>Quizartinib 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.</p> Methods <p>Plasma 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.</p> Results <p>The developed UPLC-MS/MS method demonstrated high accuracy and precision with a linear range of 6 to 200&#xa0;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&#xa0;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.</p> Conclusion <p>This 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.</p>

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

  • 期刊论文

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  • 发表日期：

    2025年8月30日

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  • Antonio Solana-Altabella,
  • Carles Iniesta-Navalón,
  • Maria Chovi-Trull,
  • Rebeca Rodriguez-Veiga,
  • Marina Lopez-Nogueroles,
  • David Martínez-Cuadrón,
  • Mayte Gil-Candel,
  • Laura Torres-Miñana,
  • Evelyn Acuña-Cruz,
  • Isabel Cano-Ferri,
  • Blanca Boluda,
  • Irene Navarro-Vicente,
  • Pilar Lloret-Madrid,
  • Eva Barragán,
  • Jose Vicente Gil,
  • Mario Rodenas-Rovira,
  • Juan Eduardo Megías-Vericat,
  • Jorge Labrador,
  • José Esteban Peris-Ribera,
  • Jose Luis Poveda-Andrés,
  • Pau Montesinos

摘要

Purpose

Quizartinib 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.

Methods

Plasma 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.

Results

The 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.

Conclusion

This 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.