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. 2022 Mar 24;12(4):526.
doi: 10.3390/jpm12040526.

Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World Setting

Camille Lenoir  1   2 , Jean Terrier  1   3   4 , Yvonne Gloor  1 , Pauline Gosselin  3   4 , Youssef Daali  1   2   4   5 , Christophe Combescure  5   6 , Jules Alexandre Desmeules  1   2   5 , Caroline Flora Samer  1   4   5 , Jean-Luc Reny  3   4   5 , Victoria Rollason  1   5
Affiliations

Impact of the Genotype and Phenotype of CYP3A and P-gp on the Apixaban and Rivaroxaban Exposure in a Real-World Setting

Camille Lenoir et al. J Pers Med. .

Abstract

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.

Keywords: DOACs; metabolism; personalized medicine; pharmacogenomics; phenotype.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Distribution of phenotype metrics in the apixaban cohort (a) MRmidazolam and (b) AUCfexofenadine.
Figure 2
Figure 2
Distribution of phenotype metrics in the rivaroxaban cohort (a) MRmidazolam and (b) AUCfexofenadine.
Figure 3
Figure 3
Blood concentrations normalized by the dosing regimen of (a) apixaban (b) rivaroxaban once daily and (c) and rivaroxaban twice daily. Each black line corresponds to an individual, and the mean ± SD is highlighted in red.
Figure 3
Figure 3
Blood concentrations normalized by the dosing regimen of (a) apixaban (b) rivaroxaban once daily and (c) and rivaroxaban twice daily. Each black line corresponds to an individual, and the mean ± SD is highlighted in red.
See this image and copyright information in PMC

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