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

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.