Work

15th Congress of the European Association for Clinical Pharmacology and Therapeutics (EACPT)

Year: 2022

Type: article

Abstract: Introduction: Apixaban and rivaroxaban, two oral direct factor Xa inhibitors (DOACs), have become an alternative to vitamin K antagonists because of their ease of use.However, safety and efficacy concerns have emerged with the availability of real-world data, particularly regarding their concomitant use with other drugs which may cause bleeding or with CYP3A and/or P-gp modulators.While age, weight and renal function are known factors for dose adjustment, CYP3A/P-gp genotypic and phenotypic activities are not routinely considered although they are involved in their metabolism and transport.Objectives: We aimed to determine whether CYP3A/P-gp genotypes and phenotypic activities could have a significant impact on apixaban and rivaroxaban blood exposure.Methods: This real-life observational study included 164 and 136 hospitalized patients treated with apixaban or rivaroxaban, respectively.CYP3A and P-gp phenotypic activities were assessed with the Geneva cocktail administered orally on the day of the study.Capillary blood samples were collected at t0 and 2h, 3h and 6h after cocktail administration to assess OH-midazolam/midazolam (CYP3A) metabolic ratios (MR) and fexofenadine (P-gp) AUC, and to assess apixaban and rivaroxaban blood concentrations.CYP3A and P-gp genetic polymorphisms were also measured.Results: Substantial interindividual variability was observed in dosenormalized blood concentrations and AUC of apixaban (117.4±55.9ng/ mL) and rivaroxaban (once a day: 21.3±12.4ng/mL and twice a day: 28.3 ±8.9 ng/mL), as well as CYP3A (0.45±0.42 for apixaban cohort and 0.44 ±0.44 for rivaroxaban cohort) and P-gp (222.8±219.4for apixaban cohort and 200.1±150 for rivaroxaban cohort) phenotypic activities.A linear mixed model for apixaban and rivaroxaban AUC predicted 40% and 18% of the variability, respectively.The covariables were the weight,Log10(AUCfexofenadine) reflecting P-gp activity (169.76 (79.4 to 260.12); p=0.0003) and GFR (Cockcroft) (-2.10 (-3.74 to -0.45); p=0.0127) were variables that significantly affected apixaban AUC.AUCfexofenadine per log10 (232.51 (105.69 to 359.33); p=0.0004) also had a significant impact on rivaroxaban AUC.CYP3A phenotype and SNPs tested had no significant impact on the pharmacokinetics of both molecules of both molecules.Conclusion: Our study demonstrated the significant impact of P-gp activity on apixaban and rivaroxaban blood concentrations, which could have a clinically relevant impact on drug response.P-gp activity could therefore be considered a relevant factor for DOACs' dose adjustment in the future.

Source: European Journal of Clinical Pharmacology

DOI: 10.1007/s00228-022-03333-y