Avacopan, a novel oral therapy for antineutrophil cytoplasmic antibody-associated vasculitis (ANCA-AAV), has changed treatment paradigms for this rare but serious disease. However, until now, a validated technique for measuring avacopan levels in patients’ plasma—a critical need for therapeutic drug monitoring and pharmacokinetic studies—was lacking. As reported by Science Direct in the Elsevier Journal of Pharmaceutical and Biomedical Analysis, this gap has been addressed by Blondel et al., who present the first fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for avacopan quantification in human plasma.
Why Avacopan Monitoring Matters
ANCA-AAV, which includes granulomatosis with polyangiitis and microscopic polyangiitis, is characterized by inflammation of blood vessels and can lead to organ damage. Avacopan, a C5a receptor antagonist, has demonstrated efficacy over traditional corticosteroids, with fewer side effects and improved kidney outcomes. Yet, real-world pharmacokinetic (PK) data is limited, partly due to the absence of a reliable bioanalytical method. With avacopan’s metabolism heavily influenced by food intake, drug interactions (notably via CYP3A4), and patient-specific factors like age and organ function, monitoring plasma levels is crucial for optimizing therapy.
Method Development and Validation
The team developed a rapid and robust LC-MS/MS assay using [2H4]-avacopan as an internal standard. Plasma samples underwent protein precipitation, followed by separation on a C18 column and detection using electrospray ionization on a triple quadrupole mass spectrometer. The method demonstrated excellent linearity across 10–800 ng/mL, with both intra- and inter-day precision and accuracy within acceptable limits (<15%). Matrix effects and extraction recovery were negligible, and the method showed no interference from commonly co-administered drugs.
Stability studies confirmed avacopan’s resilience under various storage and handling conditions, ensuring reliability in routine clinical settings. The assay’s lower limit of quantification was sensitive enough to capture even the lowest drug concentrations observed in patient samples.
Clinical Application and Insights
Applying the method to plasma from 16 patients treated for ANCA-AAV, the researchers observed significant variability in avacopan levels—a finding consistent with known interindividual differences in absorption and metabolism. For instance, liver function and adherence to food intake recommendations influenced drug exposure, while renal impairment had little effect due to avacopan’s biliary excretion.
Peak and trough concentrations in patients aligned with those reported in healthy volunteers, validating the method’s clinical relevance. Importantly, the method maintained accuracy even when samples required dilution, reflecting its suitability for diverse clinical scenarios.
Conclusion
This LC-MS/MS method marks a significant advance for clinicians and researchers managing ANCA-AAV. It enables precise, rapid, and reliable measurement of avacopan in plasma, supporting therapeutic drug monitoring, PK/PD studies, and individualized patient care. As avacopan use expands, this tool will facilitate a deeper understanding of its pharmacology in real-world populations and help optimize outcomes for patients with vasculitis.
