Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach
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| Název: | Effect of Clarithromycin, a Strong CYP3A and P-glycoprotein Inhibitor, on the Pharmacokinetics of Edoxaban in Healthy Volunteers and the Evaluation of the Drug Interaction with Other Oral Factor Xa Inhibitors by a Microdose Cocktail Approach |
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| Autoři: | Alexander Lenard, Simon A. Hermann, Felicitas Stoll, Juergen Burhenne, Kathrin I. Foerster, Gerd Mikus, Andreas D. Meid, Walter E. Haefeli, Antje Blank |
| Zdroj: | Cardiovasc Drugs Ther |
| Informace o vydavateli: | Springer Science and Business Media LLC, 2023. |
| Rok vydání: | 2023 |
| Témata: | Male, Adult, Pyridines, Pyridones, Administration, Oral, Middle Aged, Healthy Volunteers, 3. Good health, Thiazoles, Young Adult, Rivaroxaban, Clarithromycin, Area Under Curve, Humans, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A, Pyrazoles, Original Article, Drug Interactions, Female, ATP Binding Cassette Transporter, Subfamily B, Member 1, Healthy volunteers, Area Under Curve [MeSH], Pyridones/blood [MeSH], ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism [MeSH], Thiazoles/blood [MeSH], Rivaroxaban/pharmacokinetics [MeSH], Pyridones/administration, Thiazoles/pharmacokinetics [MeSH], Administration, Oral [MeSH], Male [MeSH], Cytochrome P-450 CYP3A Inhibitors/pharmacology [MeSH], Drug Interactions [MeSH], Healthy Volunteers [MeSH], Pyrazoles/blood [MeSH], Factor Xa Inhibitors/pharmacokinetics [MeSH], Thiazoles/administration, Factor Xa inhibitors, Cytochrome P-450 CYP3A/metabolism [MeSH], Pyrazoles/pharmacokinetics [MeSH], ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists, Female [MeSH], Pyridines/pharmacology [MeSH], Pyridones/pharmacokinetics [MeSH], Adult [MeSH], Humans [MeSH], Microdose, Pyrazoles/pharmacology [MeSH], Pyridines/administration, Drug-drug interaction, Factor Xa Inhibitors/administration, Middle Aged [MeSH], Clarithromycin/pharmacokinetics [MeSH], Pyrazoles/administration, Pyridines/pharmacokinetics [MeSH], Clarithromycin/pharmacology [MeSH], Pyridines/blood [MeSH], Young Adult [MeSH], Clarithromycin/administration, Thiazoles/pharmacology [MeSH], Rivaroxaban/administration, Factor Xa Inhibitors |
| Popis: | Purpose We assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose. Methods In an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (μ-FXaI; 25 μg apixaban, 50 μg edoxaban, and 25 μg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated. Plasma concentrations of study drugs were quantified using validated ultra-performance liquid chromatography–tandem mass spectrometry methods. Results Therapeutic clarithromycin doses increased the exposure of a therapeutic 60 mg dose of edoxaban with a geometric mean ratio (GMR) of the area under the plasma concentration-time curve (AUC) of 1.53 (90 % CI: 1.37–1.70; p < 0.0001). Clarithromycin also increased the GMR (90% CI) of the exposure of microdosed FXaI apixaban to 1.38 (1.26–1.51), edoxaban to 2.03 (1.84–2.24), and rivaroxaban to 1.44 (1.27–1.63). AUC changes observed for the therapeutic edoxaban dose were significantly smaller than those observed with the microdose (p < 0.001). Conclusion Clarithromycin increases FXaI exposure. However, the magnitude of this drug interaction is not expected to be clinically relevant. The edoxaban microdose overestimates the extent of the drug interaction with the therapeutic dose, whereas AUC ratios for apixaban and rivaroxaban were comparable to the interaction with therapeutic doses as reported in the literature. Trial Registration EudraCT Number: 2018-002490-22 |
| Druh dokumentu: | Article Other literature type |
| Jazyk: | English |
| ISSN: | 1573-7241 0920-3206 |
| DOI: | 10.1007/s10557-023-07443-2 |
| Přístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/36870039 https://repository.publisso.de/resource/frl:6508933 |
| Rights: | CC BY URL: http://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) . |
| Přístupové číslo: | edsair.doi.dedup.....683480ad238553ba9663b99efd3fb854 |
| Databáze: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Purpose We assessed the differential effect of clarithromycin, a strong inhibitor of cytochrome P450 (CYP) 3A4 and P-glycoprotein, on the pharmacokinetics of a regular dose of edoxaban and on a microdose cocktail of factor Xa inhibitors (FXaI). Concurrently, CYP3A activity was determined with a midazolam microdose. Methods In an open-label fixed-sequence trial in 12 healthy volunteers, the pharmacokinetics of a microdosed FXaI cocktail (μ-FXaI; 25 μg apixaban, 50 μg edoxaban, and 25 μg rivaroxaban) and of 60 mg edoxaban before and during clarithromycin (2 x 500 mg/d) dosed to steady-state was evaluated. Plasma concentrations of study drugs were quantified using validated ultra-performance liquid chromatography–tandem mass spectrometry methods. Results Therapeutic clarithromycin doses increased the exposure of a therapeutic 60 mg dose of edoxaban with a geometric mean ratio (GMR) of the area under the plasma concentration-time curve (AUC) of 1.53 (90 % CI: 1.37–1.70; p < 0.0001). Clarithromycin also increased the GMR (90% CI) of the exposure of microdosed FXaI apixaban to 1.38 (1.26–1.51), edoxaban to 2.03 (1.84–2.24), and rivaroxaban to 1.44 (1.27–1.63). AUC changes observed for the therapeutic edoxaban dose were significantly smaller than those observed with the microdose (p < 0.001). Conclusion Clarithromycin increases FXaI exposure. However, the magnitude of this drug interaction is not expected to be clinically relevant. The edoxaban microdose overestimates the extent of the drug interaction with the therapeutic dose, whereas AUC ratios for apixaban and rivaroxaban were comparable to the interaction with therapeutic doses as reported in the literature. Trial Registration EudraCT Number: 2018-002490-22 |
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| ISSN: | 15737241 09203206 |
| DOI: | 10.1007/s10557-023-07443-2 |