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Simultaneous Determination of Imatinib, Dasatinib, and Nilotinib by Liquid Chromatography-Tandem Mass Spectrometry
Aneta Wojnicz1, Beatriz Colom-Fernández, Juan L Steegmann
1*Instituto-Fundación Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain;†Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain;‡Servicio de Farmacología Clínica, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain;§Servicio de Inmunología, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain; and¶Servicio de Hematología, Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
Background:
Imatinib, dasatinib, and nilotinib are tyrosine kinase inhibitors (TKIs) used as first-line treatment of chronic myeloid leukemia. Therapeutic drug monitoring is important to achieve treatment efficacy in the case of imatinib and nilotinib, and to control toxicity in the case of dasatinib. New high-sensitivity methods to monitor those drugs are needed, especially for dasatinib. Thus, a simple method to determine plasma levels of imatinib, dasatinib, and nilotinib for application in clinical practice was developed.
Methods:
TKIs were eluted with a Poroshell 120 EC-C18 column (2.1 × 75 mm, 2.7 μm) at 0.5 mL/min and 60°C, under gradient conditions through a mobile phase consisting of 4 mmol/L ammonium formate, pH 3.2 (65%), and acetonitrile (35%). TKIs were detected and quantified by liquid chromatography in tandem with mass spectrometry (LC/MS-MS) with positive electrospray ionization and analytes were extracted using solid phase extraction (Versaplate-SCX). Internal standards were isotope-labeled for each analyte.
Results:
The method was linear in the range of 2.5-5000 ng/mL for imatinib, 0.75-400 ng/mL for dasatinib, and 2-4000 ng/mL for nilotinib. The validation assays for accuracy and precision, matrix effect, extraction recovery, carryover, and stability of the samples for all the TKIs were appropriate according to regulatory agencies. Furthermore, imatinib plasma samples, stored for 4 years at -80°C were quite stable in approximately half of the samples.
Conclusions:
The method enables rapid quantification of TKI concentrations and is being applied to therapeutic drug monitoring to adjust dose and to manage adverse reactions in clinical practice.
Insights
A new method accurately measures imatinib, dasatinib, and nilotinib plasma levels for chronic myeloid leukemia treatment. This aids therapeutic drug monitoring to optimize efficacy and manage toxicity.
Area of Science:
- Pharmacology
- Analytical Chemistry
- Oncology
Background:
- Imatinib, dasatinib, and nilotinib are key tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML).
- Therapeutic drug monitoring (TDM) is crucial for optimizing TKI efficacy and managing toxicity, particularly for dasatinib.
- There is a need for sensitive methods to monitor these TKI plasma levels in clinical settings.
Purpose of the Study:
- To develop a simple and sensitive method for quantifying imatinib, dasatinib, and nilotinib in human plasma.
- To enable accurate therapeutic drug monitoring for CML patients treated with these TKIs.
Main Methods:
- Liquid chromatography-tandem mass spectrometry (LC/MS-MS) with positive electrospray ionization was employed.
- Solid-phase extraction (SPE) was used for analyte extraction, with isotope-labeled internal standards.
- Separation was achieved using a Poroshell 120 EC-C18 column under gradient elution conditions.
Main Results:
- The method demonstrated linearity across wide concentration ranges for all three TKIs.
- Validation assays confirmed accuracy, precision, and appropriate matrix effects, extraction recovery, carryover, and stability.
- Imatinib samples showed good stability even after 4 years of storage at -80°C.
Conclusions:
- A robust LC/MS-MS method for rapid TKI quantification has been successfully developed.
- This method is suitable for routine therapeutic drug monitoring in clinical practice.
- It supports dose adjustment and adverse reaction management for CML patients.
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