{"title":"Inflammation-mediated drug interactions of olokizumab and cytochrome P450 activities in patients with rheumatoid arthritis.","authors":"Svetlana Agachi, Marina Beloukhova, Diane Mould, Maria Lemak, Sergey Grishin, Mikhail Samsonov","doi":"10.1111/bcp.16175","DOIUrl":null,"url":null,"abstract":"<p><strong>Aims: </strong>In patients with rheumatoid arthritis (RA), interleukin (IL)-6 affects the activity of cytochrome P450 (CYP) enzymes. Treatment with anti-IL-6 therapy can reverse the IL-6-mediated downregulation of CYP enzymes, resulting in changes in plasma levels of CYP substrates. The primary objective of this study was to evaluate the impact of the IL-6 inhibitor olokizumab on the pharmacokinetics of CYP probe substrates in subjects with active RA.</p><p><strong>Methods: </strong>Seventeen patients with active RA were orally administered a phenotyping cocktail of midazolam (CYP3A4 substrate), omeprazole (CYP2C19 substrate), warfarin (CYP2C9 substrate) and caffeine (CYP1A2 substrate) alone and 2 weeks after a single subcutaneous injection of 128 mg olokizumab. The pharmacokinetic parameters of each substrate were calculated using noncompartmental analysis.</p><p><strong>Results: </strong>Sixteen of 17 enrolled patients received the complete doses of the cocktail drugs and olokizumab and were eligible for the pharmacokinetic evaluations. After single-dose administration of olokizumab, the exposure of midazolam and omeprazole decreased by 30-33% and 26-32%, respectively, compared to when the substrates were administered along via cocktail. In the presence of olokizumab, caffeine exposure increased by 19-23% compared to caffeine administration alone. There were no significant changes in S-warfarin exposure.</p><p><strong>Conclusion: </strong>In patients with active RA, olokizumab potentially reverses the IL-6-mediated suppression of CYP3A4 and CYP2C19. According to FDA guidance, olokizumab is considered a weak inducer of CYP3A4 and CYP2C19.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"British journal of clinical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/bcp.16175","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
Aims: In patients with rheumatoid arthritis (RA), interleukin (IL)-6 affects the activity of cytochrome P450 (CYP) enzymes. Treatment with anti-IL-6 therapy can reverse the IL-6-mediated downregulation of CYP enzymes, resulting in changes in plasma levels of CYP substrates. The primary objective of this study was to evaluate the impact of the IL-6 inhibitor olokizumab on the pharmacokinetics of CYP probe substrates in subjects with active RA.
Methods: Seventeen patients with active RA were orally administered a phenotyping cocktail of midazolam (CYP3A4 substrate), omeprazole (CYP2C19 substrate), warfarin (CYP2C9 substrate) and caffeine (CYP1A2 substrate) alone and 2 weeks after a single subcutaneous injection of 128 mg olokizumab. The pharmacokinetic parameters of each substrate were calculated using noncompartmental analysis.
Results: Sixteen of 17 enrolled patients received the complete doses of the cocktail drugs and olokizumab and were eligible for the pharmacokinetic evaluations. After single-dose administration of olokizumab, the exposure of midazolam and omeprazole decreased by 30-33% and 26-32%, respectively, compared to when the substrates were administered along via cocktail. In the presence of olokizumab, caffeine exposure increased by 19-23% compared to caffeine administration alone. There were no significant changes in S-warfarin exposure.
Conclusion: In patients with active RA, olokizumab potentially reverses the IL-6-mediated suppression of CYP3A4 and CYP2C19. According to FDA guidance, olokizumab is considered a weak inducer of CYP3A4 and CYP2C19.
期刊介绍:
Published on behalf of the British Pharmacological Society, the British Journal of Clinical Pharmacology features papers and reports on all aspects of drug action in humans: review articles, mini review articles, original papers, commentaries, editorials and letters. The Journal enjoys a wide readership, bridging the gap between the medical profession, clinical research and the pharmaceutical industry. It also publishes research on new methods, new drugs and new approaches to treatment. The Journal is recognised as one of the leading publications in its field. It is online only, publishes open access research through its OnlineOpen programme and is published monthly.