Abstract
Fostamatinib is a prodrug of the active metabolite tamatinib, which is a spleen tyrosine kinase (Syk) inhibitor used in the treatment of primary chronic adult immune thrombocytopenia and rheumatoid arthritis. A highly sensitive, rapid, reliable, and green method was developed and validated using ultra-performance liquid chromatography and tandem mass spectrometry (UPLC–MS/MS) for quantification of tamatinib in rat plasma. Ibrutinib was used as internal standard and liquid–liquid extraction was applied using tert-butyl methyl ether. The analyte was separated on an AcquityTM CSH C18 (2.1 mm × 100 mm, 1.7 µm) column using mobile phase consisting of 10 mM ammonium acetate and acetonitrile (10:90) and the flow rate was 0.25 mL/min. Electrospray ionization (ESI) was carried out in positive mode. Quantitation of tamatinib and the IS was performed using multiple reaction monitoring mode with precursor-to-product transitions of m/z 471.1 > 122.0 and m/z 441.1 > 84.0, respectively. The calibration range was 0.1–1000.0 ng/mL and the linearity of the method was ≥0.997. The developed method greenness was investigated. All principal parameters for the method, including linearity, accuracy, precision, recovery, and stability, were within acceptable ranges. Tamatinib pharmacokinetic study in rats was successfully carried out using the developed method.
Highlights
Fostamatinib is an oral spleen tyrosine kinase (Syk) inhibitor that is effective in the treatment of malignant clones through inhibition of antigen-dependent BCR signals [1,2]
Fostamatinib is a prodrug of the active compound, tamatinib, which is a relatively selective Syk inhibitor used to treat rheumatoid arthritis [3,4], especially in patients with poor therapeutic response to methotrexate [5]
The efficiency of analytical methods to separate the analyte and IS depends on its sensitivity, which is represented by low limit of detection (LLOD) or low limit of quantitation (LLOQ)
Summary
Fostamatinib is an oral Syk inhibitor that is effective in the treatment of malignant clones through inhibition of antigen-dependent BCR signals [1,2]. Fostamatinib is a prodrug of the active compound, tamatinib, which is a relatively selective Syk inhibitor used to treat rheumatoid arthritis [3,4], especially in patients with poor therapeutic response to methotrexate [5]. The drug can induce time- and dose-dependent decline in cell viability that is linked to apoptosis activation. This activity causes a reduction in tumor growth and was enhanced in combinations with other treatments, including bortezomib, rituximab, and dexamethasone [10]. Dropout and subsequent loss of efficacy during fostamatinib treatment increased with the increases of its dose [3]
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