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Cytochrome P450 activity in rheumatoid arthritis patients during continuous IL-6 receptor antagonist therapy

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  • Additional Information
    • Publication Date:
      2023
    • Collection:
      University of Southern Denmark: Research Output / Syddansk Universitet
    • Abstract:
      BACKGROUND: Inflammation suppresses cytochrome P450 (CYP) enzyme activity, and single-dose interleukin 6 receptor antagonists (anti-IL-6R) reverse this effect. Here, we assess the impact of continuous anti-IL-6R therapy in patients with rheumatoid arthritis. METHODS: In a clinical pharmacokinetic trial, the Basel cocktail was administered before and after 3 and 12 weeks of anti-IL-6R therapy to assess CYP enzyme activity (registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13 th, 2021). In a retrospective study, the 4β-hydroxycholesterol/cholesterol ratio was measured as a biomarker for CYP3A4 activity before and after 3 and 6 months of anti-IL-6R therapy. The control group was patients initiating a tumor necrosis factor alfa (TNF-α) inhibitor. RESULTS: In the clinical pharmacokinetic trial (n = 3), midazolam metabolic ratio (CYP3A4) was inconclusive due to the limited sample size. Midazolam AUC and C max indicate a weak impact on CYP3A4 activity after 3 weeks of anti-IL-6R therapy compared to baseline (AUC geometric mean ratio (GMR): 0.80, 95% CI: 0.64-0.99 and C max GMR: 0.58, 95% CI: 0.37-0.91), which returns to baseline levels after 12 weeks of therapy (AUC GMR 1.02, 95% CI: 0.72-1.46 and C max GMR 1.03, 95% CI 0.72-1.47). No effect on the 4β-hydroxycholesterol/cholesterol ratio was observed in the retrospective study. CONCLUSION: Based on sparse data from three patients, continuous anti-IL-6R therapy seems to cause an acute but transient increase in CYP3A4 activity in rheumatoid arthritis patients, which may be due to a normalization of the inflammation-suppressed CYP activity. Further studies are warranted to understand the mechanism behind this putative transient effect. Trial registration Registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13th, 2021.
    • File Description:
      application/pdf
    • Accession Number:
      10.1007/s00228-023-03578-1
    • Online Access:
      https://portal.findresearcher.sdu.dk/da/publications/325a5b67-5f1d-4fed-aa81-fe7eac880332
      https://doi.org/10.1007/s00228-023-03578-1
      https://findresearcher.sdu.dk/ws/files/252091705/Open_Access_Version.pdf
    • Rights:
      info:eu-repo/semantics/openAccess
    • Accession Number:
      edsbas.69FCC583