Development and Validation of a LC-MS/MS Method for Ripretinib and Its Metabolite: Example of a Journey From...

Area of Science:

• Analytical Chemistry
• Pharmacology
• Environmental Chemistry

Background:

• Therapeutic drug monitoring (TDM) of protein kinase inhibitors is crucial for patient treatment.
• Ripretinib is a targeted therapy requiring precise dosage management.
• Developing sustainable and environmentally friendly analytical methods is an increasing priority in pharmaceutical analysis.

Purpose of the Study:

• To develop and validate a UPLC-MS/MS method for quantifying ripretinib and its active metabolite, N-desmethyl-ripretinib, in human plasma.
• To ensure the method is environmentally sustainable, aligning with green chemistry principles.
• To provide a reliable tool for therapeutic drug monitoring in clinical and preclinical settings.

Main Methods:

• Ultra-Performance Liquid Chromatography-tandem Mass Spectrometry (UPLC-MS/MS) was employed for separation and detection.
• Stable isotopic internal standards were used for accurate quantification.
• Method optimization focused on mobile phase composition (water with acetic acid/formic acid, acetonitrile) and positive electrospray ionization.
• Multiple reaction monitoring (MRM) transitions were established for ripretinib and N-desmethyl-ripretinib.
• Validation was performed according to International Council for Harmonisation (ICH) guidelines.

Main Results:

• The UPLC-MS/MS method was successfully optimized and validated for ripretinib and N-desmethyl-ripretinib in human plasma.
• The method demonstrated high sensitivity and specificity, suitable for TDM.
• Greenness assessment using the AGREE metric indicated the method's environmental advantage over previous approaches.
• The validated method was effectively applied to monitor drug concentrations in clinical and preclinical samples.

Conclusions:

• A validated, environmentally friendly UPLC-MS/MS method for ripretinib and N-desmethyl-ripretinib TDM has been established.
• This method supports precise drug concentration monitoring, aiding in personalized medicine approaches for patients treated with ripretinib.
• The study highlights the successful integration of green chemistry principles into pharmaceutical analysis without compromising analytical performance.