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Here, we assess the impact of continuous anti-IL-6R therapy in patients with rheumatoid arthritis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>(registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>th<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>, 2021)<\/jats:italic>\n                      . In a retrospective study, the 4\u03b2-hydroxycholesterol\/cholesterol ratio was measured as a biomarker for CYP3A4 activity before and after 3 and 6 months of anti-IL-6R therapy.\u00a0The control group was patients initiating a tumor necrosis factor alfa (TNF-\u03b1) inhibitor.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In the clinical pharmacokinetic trial (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20093), midazolam metabolic ratio (CYP3A4) was inconclusive due to the limited sample size. Midazolam AUC and\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      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\u20130.99 and\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      GMR: 0.58, 95% CI: 0.37\u20130.91), which returns to baseline levels after 12 weeks of therapy (AUC GMR 1.02, 95% CI: 0.72\u20131.46 and\n                      <jats:italic>C<\/jats:italic>\n                      <jats:sub>max<\/jats:sub>\n                      GMR 1.03, 95% CI 0.72\u20131.47). No effect on the 4\u03b2-hydroxycholesterol\/cholesterol ratio was observed in the retrospective study.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>\n                      <jats:italic>Trial registration\u00a0<\/jats:italic>\n                      Registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13th, 2021.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00228-023-03578-1","type":"journal-article","created":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T07:02:23Z","timestamp":1697180543000},"page":"1687-1698","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Cytochrome P450 activity in rheumatoid arthritis patients during continuous IL-6 receptor antagonist therapy"],"prefix":"10.1007","volume":"79","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7574-0909","authenticated-orcid":false,"given":"Ann-Cathrine Dalg\u00e5rd","family":"Dunvald","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1111-8050","authenticated-orcid":false,"given":"Kasper","family":"S\u00f8ltoft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekta","family":"Sheetal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3946-5919","authenticated-orcid":false,"given":"S\u00f8ren Andreas","family":"Just","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida Emilie Brejning","family":"Frederiksen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5657-405X","authenticated-orcid":false,"given":"Flemming","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2589-738X","authenticated-orcid":false,"given":"Dorte Aalund","family":"Olsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6668-4714","authenticated-orcid":false,"given":"Jonna Skov","family":"Madsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9473-5072","authenticated-orcid":false,"given":"Oliver","family":"Hendricks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4698-4389","authenticated-orcid":false,"given":"Tore Bjerregaard","family":"Stage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,10,13]]},"reference":[{"issue":"7","key":"3578_CR1","first-page":"S128","volume":"20","author":"A Gibofsky","year":"2014","unstructured":"Gibofsky A (2014) Epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis: a synopsis. 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The prospective clinical pharmacokinetic trial was approved by the Regional Scientific Ethics Committee of Southern Denmark (identifier S-20210010), the Danish Medicines Agency (identifier 2021013658), and registered in the EudraCT database (identifier 2020\u2013005998-27) and the ClinicalTrials.gov database (identifier NCT04842981). The study complied with Good Clinical Practice (GCP) and was monitored by the GCP unit at Odense University Hospital. Trial subjects were included following written, informed consent. The retrospective study was approved by the Regional Ethics Committee of Southern Denmark (identifier S-20210097). Patients gave written informed consent for the biological material and personal information to be stored and used for future unspecified research when the biobank samples were collected.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}},{"value":"A.C.D. has given paid lectures for Astellas Pharma. T.S. has given paid lectures for Pfizer and Eisai and consulted for Pfizer. All are unrelated to the work reported in this paper. K.S., E.S., S.A.J., I.E.B.F., F.N., D.A.O., J.S.M., and O.H. report no conflicts of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}