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Multi-Matrix LC-MS/MS Validation of Methotrexate Polyglutamates: Comparison of VAMS, DBS, and Conventional Blood
Arkadiusz Kocur1, Marek Kajfasz2, Aleksandra Mikulska1
1Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland.
New methods using capillary blood, like volumetric absorptive microsampling (VAMS) and dried blood spots (DBS), accurately measure methotrexate polyglutamates (MTXPGs) for rheumatoid arthritis (RA) monitoring. These less invasive techniques offer comparable results to traditional blood draws, aiding decentralized drug exposure assessment.
Area of Science:
- Pharmacokinetics and Drug Monitoring
- Analytical Chemistry
- Rheumatology
Background:
- Methotrexate (MTX) is a primary treatment for rheumatoid arthritis (RA), but patient response varies, necessitating reliable biomarkers.
- Intracellular methotrexate polyglutamates (MTXPGs) in red blood cells (RBCs) indicate long-term drug exposure but require invasive venous sampling.
- Developing less invasive methods for MTXPG measurement is crucial for improved patient monitoring and adherence.
Purpose of the Study:
- To develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measuring MTXPGs in capillary blood.
- To assess the feasibility of using volumetric absorptive microsampling (VAMS) and dried blood spots (DBS) for MTXPG analysis.
- To compare MTXPG measurements in VAMS and DBS with traditional matrices like RBCs and whole blood (WB).
Main Methods:
- A multi-matrix LC-MS/MS method was developed and validated according to ICH M10 guidelines.
- Samples analyzed included red blood cells (RBCs), whole blood (WB), VAMS, and DBS.
- Method validation involved Passing-Bablok regression, Bland-Altman analysis, Spearman correlation, and stability testing.
Main Results:
- Strong agreement was observed between VAMS and DBS for total MTXPG measurements (slopes 0.95-1.07, bias -4.21% to 0.36%).
- Capillary matrices showed significant differences compared to RBCs, with higher MTXPG levels in erythrocytes.
- Whole blood demonstrated closer agreement with microsampling methods than RBCs; stability varied by matrix and MTXPG chain length.
Conclusions:
- VAMS and DBS are interchangeable capillary sampling methods for MTXPG measurement in RA patients.
- Matrix-specific differences must be considered when comparing capillary results to RBC-based reference values.
- This validated method supports decentralized MTXPG monitoring, but further studies are needed to link thresholds with clinical outcomes.
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