Amelie Leutzendorff, Valentin al Jalali, Martin Bauer, Iris K. Minichmayr, Birgit Reiter, Michael Wölfl - Duchek, Alina Nussbaumer-Pröll, Maria Weber, Sabine Eberl, Marie Spies, Maysa Sarhan, Johannes Geilen, Alexander Walther, Daniel Drai, Markus Zeitlinger
{"title":"氯米帕明、育亨宾和氯米帕明/育亨宾复方制剂的单剂量和稳态药代动力学:临床药物相互作用研究。","authors":"Amelie Leutzendorff, Valentin al Jalali, Martin Bauer, Iris K. Minichmayr, Birgit Reiter, Michael Wölfl - Duchek, Alina Nussbaumer-Pröll, Maria Weber, Sabine Eberl, Marie Spies, Maysa Sarhan, Johannes Geilen, Alexander Walther, Daniel Drai, Markus Zeitlinger","doi":"10.1111/bcp.16274","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Aims</h3>\n \n <p>Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>A prospective, open-labelled, single-centre, pharmacokinetic (PK) drug–drug interaction study was performed in 15 healthy male subjects. Single-dose and steady-state PK were investigated using noncompartmental analysis after mono- and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80–125%.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination <i>vs</i>. monotherapy) was 112% (90% confidence interval: 104–120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112–168%). The study drugs were safe and well tolerated as mono- and combination therapy, with no major adverse events reported.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>A PK assessment of clomipramine and yohimbine indicated a clinically significant drug–drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI-related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25–<2-fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies.</p>\n </section>\n </div>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"91 3","pages":"808-816"},"PeriodicalIF":3.1000,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Single-dose and steady-state pharmacokinetics of clomipramine, yohimbine and clomipramine/yohimbine combination: A clinical drug–drug interaction study\",\"authors\":\"Amelie Leutzendorff, Valentin al Jalali, Martin Bauer, Iris K. Minichmayr, Birgit Reiter, Michael Wölfl - Duchek, Alina Nussbaumer-Pröll, Maria Weber, Sabine Eberl, Marie Spies, Maysa Sarhan, Johannes Geilen, Alexander Walther, Daniel Drai, Markus Zeitlinger\",\"doi\":\"10.1111/bcp.16274\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Aims</h3>\\n \\n <p>Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>A prospective, open-labelled, single-centre, pharmacokinetic (PK) drug–drug interaction study was performed in 15 healthy male subjects. Single-dose and steady-state PK were investigated using noncompartmental analysis after mono- and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80–125%.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination <i>vs</i>. monotherapy) was 112% (90% confidence interval: 104–120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112–168%). The study drugs were safe and well tolerated as mono- and combination therapy, with no major adverse events reported.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusion</h3>\\n \\n <p>A PK assessment of clomipramine and yohimbine indicated a clinically significant drug–drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI-related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25–<2-fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies.</p>\\n </section>\\n </div>\",\"PeriodicalId\":9251,\"journal\":{\"name\":\"British journal of clinical pharmacology\",\"volume\":\"91 3\",\"pages\":\"808-816\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-10-21\",\"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://onlinelibrary.wiley.com/doi/10.1111/bcp.16274\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"British journal of clinical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/bcp.16274","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Single-dose and steady-state pharmacokinetics of clomipramine, yohimbine and clomipramine/yohimbine combination: A clinical drug–drug interaction study
Aims
Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile.
Methods
A prospective, open-labelled, single-centre, pharmacokinetic (PK) drug–drug interaction study was performed in 15 healthy male subjects. Single-dose and steady-state PK were investigated using noncompartmental analysis after mono- and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80–125%.
Results
The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination vs. monotherapy) was 112% (90% confidence interval: 104–120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112–168%). The study drugs were safe and well tolerated as mono- and combination therapy, with no major adverse events reported.
Conclusion
A PK assessment of clomipramine and yohimbine indicated a clinically significant drug–drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI-related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25–<2-fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies.
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.