Your browser doesn't support javascript.
loading
Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World Setting.
Lenoir, Camille; Terrier, Jean; Gloor, Yvonne; Gosselin, Pauline; Daali, Youssef; Combescure, Christophe; Desmeules, Jules Alexandre; Samer, Caroline Flora; Reny, Jean-Luc; Rollason, Victoria.
Afiliação
  • Lenoir C; Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, 1205 Geneva, Switzerland.
  • Terrier J; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1206 Geneva, Switzerland.
  • Gloor Y; Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, 1205 Geneva, Switzerland.
  • Gosselin P; Department of Medicine, Division of General Internal Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland.
  • Daali Y; Geneva Platelet Group, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland.
  • Combescure C; Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, 1205 Geneva, Switzerland.
  • Desmeules JA; Department of Medicine, Division of General Internal Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland.
  • Samer CF; Geneva Platelet Group, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland.
  • Reny JL; Department of Anaesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, 1205 Geneva, Switzerland.
  • Rollason V; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1206 Geneva, Switzerland.
J Pers Med ; 12(4)2022 Mar 24.
Article em En | MEDLINE | ID: mdl-35455642
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 AUC0−6h of fexofenadine, respectively. Relevant CYP3A and ABCB1 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 (p < 0.001) and creatinine clearance (CrCl) (p = 0.01) significantly affected apixaban AUC0−6h. P-gp activity (p < 0.001) also significantly impacted rivaroxaban AUC0−6h. The phenotypic switch (from normal to poor metabolizer) of P-gp led to an increase of apixaban and rivaroxaban AUC0−6h 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.
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: J Pers Med Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Suíça

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: J Pers Med Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Suíça