Work

Apixaban kinetics could be influenced by sex, cytochrome P450 enzymes and SLC6A2 transporter

Year: 2025

Type: article

Abstract: Apixaban is an oral anticoagulant that directly inhibit the coagulation pathway by binding to factor Xa, making it the best alternative to vitamin K inhibitors. Currently, there are no pharmacogenetic markers related to its kinetics or safety, so the objective of this study was to carry out a candidate gene study that would allow us to study 118 variants in 36 genes related to drug transport or metabolism and thus expand the existing knowledge on the pharmacogenetics of apixaban. This study included 75 healthy volunteers from three apixaban bioequivalence trials conducted at the Clinical Trials Unit of Hospital Universitario de La Princesa (UECHUP). DNA was genotyped using a ThermoFisher OpenArray of our own design. An increase in C max/ DW (dose/weight adjusted) was observed in women ( p = 0.048). No significant differences were observed based on biogeographic origin or clinical trial. An increase in t 1/2 was observed in carriers of the ABCC2 rs2273697 variant ( p = 0.031), an increase in T max in carriers of rs72552763 of SLC22A1 ( p = 0.028) and a decrease in both AUC and C max /DW in carriers of the SLC6A2 rs3785143 variant ( p = 0.020, p = 0.029, p = 0.002, respectively). Of these, only the decrease in C max /DW associated with the SLC6A2 gene was maintained in the multivariate analysis ( p multivariate(mv) = 0.027). An increase in C max /DW was observed in carriers of rs2740574 variant in CYP3A4 ( p = 0.040) and in poor metabolizers of CYP3A5 ( p = 0.022, p mv =0.027). Carriers of the rs3093200 variant in CYP4F2 showed a decrease in C max /DW ( p = 0.049, p mv =0.020). Further studies are needed to understand the involvement of these genes in apixaban kinetics. • Analysis of 118 variants in 36 genes in relation to the kinetics of apixaban. • Women show an 11 % increase in C max /DW (dose/weight adjusted) compared to men. • Poor metabolizers for CYP3A5 show a 14 % increase in C max /DW. • Carriers of SLC6A2 rs3785143 variant show a slight decrease in AUC and Cmax.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2025.118732