Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World Setting
Apixaban and rivaroxaban are the two most prescribed direct factor Xa inhibitors. With the increased use of DOACs in real-world settings, safety and efficacy concerns have emerged, particularly regarding their concomitant use with other drugs. Increasing evidence highlights drug–drug interactions wi...
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MDPI AG
2022-03-01
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| Series: | Journal of Personalized Medicine |
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| Online Access: | https://www.mdpi.com/2075-4426/12/4/526 |
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| author | Camille Lenoir Jean Terrier Yvonne Gloor Pauline Gosselin Youssef Daali Christophe Combescure Jules Alexandre Desmeules Caroline Flora Samer Jean-Luc Reny Victoria Rollason |
| author_facet | Camille Lenoir Jean Terrier Yvonne Gloor Pauline Gosselin Youssef Daali Christophe Combescure Jules Alexandre Desmeules Caroline Flora Samer Jean-Luc Reny Victoria Rollason |
| author_sort | Camille Lenoir |
| collection | DOAJ |
| description | Apixaban and rivaroxaban are the two most prescribed direct factor Xa inhibitors. With the increased use of DOACs in real-world settings, safety and efficacy concerns have emerged, particularly regarding their concomitant use with other drugs. Increasing evidence highlights drug–drug interactions with CYP3A/P-gp modulators leading to adverse events. However, current recommendations for dose adjustment do not consider CYP3A/P-gp genotype and phenotype. We aimed to determine their impact on apixaban and rivaroxaban blood exposure. Three-hundred hospitalized patients were included. CYP3A and P-gp phenotypic activities were assessed by the metabolic ratio of midazolam and AUC<sub>0–6h</sub> of fexofenadine, respectively. Relevant <i>CYP3A</i> and <i>ABCB1</i> genetic polymorphisms were also tested. Capillary blood samples collected at four time-points after apixaban or rivaroxaban administration allowed the calculation of pharmacokinetic parameters. According to the developed multivariable linear regression models, P-gp activity (<i>p</i> < 0.001) and creatinine clearance (CrCl) (<i>p</i> = 0.01) significantly affected apixaban AUC<sub>0–6h</sub>. P-gp activity (<i>p</i> < 0.001) also significantly impacted rivaroxaban AUC<sub>0–6h</sub>. The phenotypic switch (from normal to poor metabolizer) of P-gp led to an increase of apixaban and rivaroxaban AUC<sub>0–6h</sub> by 16% and 25%, respectively, equivalent to a decrease of 38 mL/min in CrCl according to the apixaban model. CYP3A phenotype and tested SNPs of CYP3A/P-gp had no significant impact. In conclusion, P-gp phenotypic activity, rather than known CYP3A/P-gp polymorphisms, could be relevant for dose adjustment. |
| first_indexed | 2024-03-09T04:31:42Z |
| format | Article |
| id | doaj.art-4edd74e5ef51455e8a8db57e9595227b |
| institution | Directory Open Access Journal |
| issn | 2075-4426 |
| language | English |
| last_indexed | 2024-03-09T04:31:42Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Personalized Medicine |
| spelling | doaj.art-4edd74e5ef51455e8a8db57e9595227b2023-12-03T13:34:59ZengMDPI AGJournal of Personalized Medicine2075-44262022-03-0112452610.3390/jpm12040526Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World SettingCamille Lenoir0Jean Terrier1Yvonne Gloor2Pauline Gosselin3Youssef Daali4Christophe Combescure5Jules Alexandre Desmeules6Caroline Flora Samer7Jean-Luc Reny8Victoria Rollason9Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, 1205 Geneva, SwitzerlandDepartment of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, 1205 Geneva, SwitzerlandDepartment of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, 1205 Geneva, SwitzerlandDepartment of Medicine, Division of General Internal Medicine, Geneva University Hospitals, 1205 Geneva, SwitzerlandDepartment of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, 1205 Geneva, SwitzerlandFaculty of Medicine, University of Geneva, 1206 Geneva, SwitzerlandDepartment of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, 1205 Geneva, SwitzerlandDepartment of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, 1205 Geneva, SwitzerlandDepartment of Medicine, Division of General Internal Medicine, Geneva University Hospitals, 1205 Geneva, SwitzerlandDepartment of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, 1205 Geneva, SwitzerlandApixaban and rivaroxaban are the two most prescribed direct factor Xa inhibitors. With the increased use of DOACs in real-world settings, safety and efficacy concerns have emerged, particularly regarding their concomitant use with other drugs. Increasing evidence highlights drug–drug interactions with CYP3A/P-gp modulators leading to adverse events. However, current recommendations for dose adjustment do not consider CYP3A/P-gp genotype and phenotype. We aimed to determine their impact on apixaban and rivaroxaban blood exposure. Three-hundred hospitalized patients were included. CYP3A and P-gp phenotypic activities were assessed by the metabolic ratio of midazolam and AUC<sub>0–6h</sub> of fexofenadine, respectively. Relevant <i>CYP3A</i> and <i>ABCB1</i> genetic polymorphisms were also tested. Capillary blood samples collected at four time-points after apixaban or rivaroxaban administration allowed the calculation of pharmacokinetic parameters. According to the developed multivariable linear regression models, P-gp activity (<i>p</i> < 0.001) and creatinine clearance (CrCl) (<i>p</i> = 0.01) significantly affected apixaban AUC<sub>0–6h</sub>. P-gp activity (<i>p</i> < 0.001) also significantly impacted rivaroxaban AUC<sub>0–6h</sub>. The phenotypic switch (from normal to poor metabolizer) of P-gp led to an increase of apixaban and rivaroxaban AUC<sub>0–6h</sub> by 16% and 25%, respectively, equivalent to a decrease of 38 mL/min in CrCl according to the apixaban model. CYP3A phenotype and tested SNPs of CYP3A/P-gp had no significant impact. In conclusion, P-gp phenotypic activity, rather than known CYP3A/P-gp polymorphisms, could be relevant for dose adjustment.https://www.mdpi.com/2075-4426/12/4/526DOACspharmacogenomicsphenotypemetabolismpersonalized medicine |
| spellingShingle | Camille Lenoir Jean Terrier Yvonne Gloor Pauline Gosselin Youssef Daali Christophe Combescure Jules Alexandre Desmeules Caroline Flora Samer Jean-Luc Reny Victoria Rollason Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World Setting Journal of Personalized Medicine DOACs pharmacogenomics phenotype metabolism personalized medicine |
| title | Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World Setting |
| title_full | Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World Setting |
| title_fullStr | Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World Setting |
| title_full_unstemmed | Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World Setting |
| title_short | Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World Setting |
| title_sort | impact of the genotype and phenotype of cyp3a and p gp on the apixaban and rivaroxaban exposure in a real world setting |
| topic | DOACs pharmacogenomics phenotype metabolism personalized medicine |
| url | https://www.mdpi.com/2075-4426/12/4/526 |
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