Felicitas Stoll, Antje Blank, Gerd Mikus, David Czock, Johanna Weiss, Marleen J Meyer-Tönnies, Katja S Gümüs, Mladen Tzvetkov, Jürgen Burhenne, Walter E Haefeli
{"title":"在健康志愿者中使用微剂量探针药物评估羟氯喹作为细胞色素 P450 (CYP) 3A 和 CYP2D6 活性的诱导剂。","authors":"Felicitas Stoll, Antje Blank, Gerd Mikus, David Czock, Johanna Weiss, Marleen J Meyer-Tönnies, Katja S Gümüs, Mladen Tzvetkov, Jürgen Burhenne, Walter E Haefeli","doi":"10.1007/s13318-023-00872-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objective: </strong>Although polypharmacy is a particular challenge in daily rheumatological practice, clinical research on the effects of hydroxychloroquine (HCQ), a commonly used drug for patients with rheumatic diseases, is sparse on cytochrome P450 (CYP)-mediated metabolism. We have shown that pre-treatment with pantoprazole does not alter HCQ absorption in healthy volunteers. In this paper, we report the effects of a single 400 mg dose of HCQ on specific CYP3A and CYP2D6 substrates in healthy volunteers.</p><p><strong>Methods: </strong>In the trial, participants were randomized into two groups (HCQ plus a 9-day course of pantoprazole, or HCQ only). As a secondary endpoint, the effects of a single oral dose of HCQ on the exposure of the oral microdosed CYP3A probe drug midazolam (30 μg) and the oral microdosed CYP2D6 probe drug yohimbine (50 μg) were studied in 23 healthy volunteers (EudraCT no. 2020-001470-30, registered 31 March 2020).</p><p><strong>Results: </strong>The exposure of the probe drugs after intake of HCQ compared with baseline values was quantified by the partial area under the plasma concentration-time curve 0-6 h after administration (AUC<sub>0-6 h</sub>) for yohimbine and the partial AUC<sub>2-4 h</sub> for midazolam. Under HCQ, yohimbine AUC<sub>0-6 h</sub> was unchanged, independent of CYP2D6 genotypes and pantoprazole exposure. Midazolam AUC<sub>2-4 h</sub> was 25% higher on the day of HCQ administration than at baseline (p = 0.0007). This significant increase was driven by the pantoprazole subgroup, which showed a 46% elevation of midazolam AUC<sub>2-4 h</sub> as compared with baseline (p < 0.0001). The ratio of midazolam to 1-OH-midazolam partial AUC<sub>2-4 h</sub> significantly increased from 3.03 ± 1.59 (baseline) to 3.60 ± 1.56 (HCQ) in the pantoprazole group (p = 0.0026).</p><p><strong>Conclusion: </strong>In conclusion, we observed an increased midazolam exposure most likely related to pantoprazole.</p>","PeriodicalId":11939,"journal":{"name":"European Journal of Drug Metabolism and Pharmacokinetics","volume":" ","pages":"101-109"},"PeriodicalIF":1.9000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10781839/pdf/","citationCount":"0","resultStr":"{\"title\":\"Evaluation of Hydroxychloroquine as a Perpetrator on Cytochrome P450 (CYP) 3A and CYP2D6 Activity with Microdosed Probe Drugs in Healthy Volunteers.\",\"authors\":\"Felicitas Stoll, Antje Blank, Gerd Mikus, David Czock, Johanna Weiss, Marleen J Meyer-Tönnies, Katja S Gümüs, Mladen Tzvetkov, Jürgen Burhenne, Walter E Haefeli\",\"doi\":\"10.1007/s13318-023-00872-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objective: </strong>Although polypharmacy is a particular challenge in daily rheumatological practice, clinical research on the effects of hydroxychloroquine (HCQ), a commonly used drug for patients with rheumatic diseases, is sparse on cytochrome P450 (CYP)-mediated metabolism. We have shown that pre-treatment with pantoprazole does not alter HCQ absorption in healthy volunteers. In this paper, we report the effects of a single 400 mg dose of HCQ on specific CYP3A and CYP2D6 substrates in healthy volunteers.</p><p><strong>Methods: </strong>In the trial, participants were randomized into two groups (HCQ plus a 9-day course of pantoprazole, or HCQ only). As a secondary endpoint, the effects of a single oral dose of HCQ on the exposure of the oral microdosed CYP3A probe drug midazolam (30 μg) and the oral microdosed CYP2D6 probe drug yohimbine (50 μg) were studied in 23 healthy volunteers (EudraCT no. 2020-001470-30, registered 31 March 2020).</p><p><strong>Results: </strong>The exposure of the probe drugs after intake of HCQ compared with baseline values was quantified by the partial area under the plasma concentration-time curve 0-6 h after administration (AUC<sub>0-6 h</sub>) for yohimbine and the partial AUC<sub>2-4 h</sub> for midazolam. Under HCQ, yohimbine AUC<sub>0-6 h</sub> was unchanged, independent of CYP2D6 genotypes and pantoprazole exposure. Midazolam AUC<sub>2-4 h</sub> was 25% higher on the day of HCQ administration than at baseline (p = 0.0007). This significant increase was driven by the pantoprazole subgroup, which showed a 46% elevation of midazolam AUC<sub>2-4 h</sub> as compared with baseline (p < 0.0001). The ratio of midazolam to 1-OH-midazolam partial AUC<sub>2-4 h</sub> significantly increased from 3.03 ± 1.59 (baseline) to 3.60 ± 1.56 (HCQ) in the pantoprazole group (p = 0.0026).</p><p><strong>Conclusion: </strong>In conclusion, we observed an increased midazolam exposure most likely related to pantoprazole.</p>\",\"PeriodicalId\":11939,\"journal\":{\"name\":\"European Journal of Drug Metabolism and Pharmacokinetics\",\"volume\":\" \",\"pages\":\"101-109\"},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10781839/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Drug Metabolism and Pharmacokinetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s13318-023-00872-2\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/12/20 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Drug Metabolism and Pharmacokinetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13318-023-00872-2","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/12/20 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Evaluation of Hydroxychloroquine as a Perpetrator on Cytochrome P450 (CYP) 3A and CYP2D6 Activity with Microdosed Probe Drugs in Healthy Volunteers.
Background and objective: Although polypharmacy is a particular challenge in daily rheumatological practice, clinical research on the effects of hydroxychloroquine (HCQ), a commonly used drug for patients with rheumatic diseases, is sparse on cytochrome P450 (CYP)-mediated metabolism. We have shown that pre-treatment with pantoprazole does not alter HCQ absorption in healthy volunteers. In this paper, we report the effects of a single 400 mg dose of HCQ on specific CYP3A and CYP2D6 substrates in healthy volunteers.
Methods: In the trial, participants were randomized into two groups (HCQ plus a 9-day course of pantoprazole, or HCQ only). As a secondary endpoint, the effects of a single oral dose of HCQ on the exposure of the oral microdosed CYP3A probe drug midazolam (30 μg) and the oral microdosed CYP2D6 probe drug yohimbine (50 μg) were studied in 23 healthy volunteers (EudraCT no. 2020-001470-30, registered 31 March 2020).
Results: The exposure of the probe drugs after intake of HCQ compared with baseline values was quantified by the partial area under the plasma concentration-time curve 0-6 h after administration (AUC0-6 h) for yohimbine and the partial AUC2-4 h for midazolam. Under HCQ, yohimbine AUC0-6 h was unchanged, independent of CYP2D6 genotypes and pantoprazole exposure. Midazolam AUC2-4 h was 25% higher on the day of HCQ administration than at baseline (p = 0.0007). This significant increase was driven by the pantoprazole subgroup, which showed a 46% elevation of midazolam AUC2-4 h as compared with baseline (p < 0.0001). The ratio of midazolam to 1-OH-midazolam partial AUC2-4 h significantly increased from 3.03 ± 1.59 (baseline) to 3.60 ± 1.56 (HCQ) in the pantoprazole group (p = 0.0026).
Conclusion: In conclusion, we observed an increased midazolam exposure most likely related to pantoprazole.
期刊介绍：
Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences.
Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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