Avaliação da farmacocinética da rivaroxabana e do polimorfismo no gene ABCG2 em voluntários sadios incluídos em estudos de bioequivalência

Abstract

Rivaroxaban is a direct oral anticoagulant used to treatment of venous thromboembolism and prevention of stroke in patients with atrial fibrillation. This drug acts as a factor Xa inhibitor in the coagulation cascade and is metabolized in the liver by CYP3A4/5 and CYP2J2 enzymes, in addition to being a substrate for P- glycoprotein and breast cancer resistance protein (BCRP). Many patients on anticoagulant therapy do not respond adequately to treatment or have adverse reactions, such as bleeding. This variability in pharmacological response may be caused by genetic polymorphism. Therefore, the main objective of this study was to evaluate the influence of genetic polymorphism on pharmacokinetic (Cmax, AUC, Cl, t1/2 and Vd) and coagulation (PT and aPTT) parameters of rivaroxaban. We included 117 healthy volunteers who participated in two bioequivalence studies with a single oral dose of 20 mg rivaroxaban, under fasting and postprandial conditions. Plasma concentrations were determined by a method developed and validated by UHPLC- MS/MS. The polymorphism in the ABCG2 421 C>A gene that encodes the BCRP transporter enzyme responsible for the efflux of rivaroxaban was evaluated. The chromatographic method developed was precise, accurate, stable and presented an adequate working range for application in a bioequivalence study. Volunteers with 421 A/A genotype, compared respectively to 421 C/A and 421 C/C, presented Vd (508.27 vs 334.45 vs 275.59 L) and t1/2 (41.04 vs 16.43 vs 15.47 h) significantly higher in the study under fasting conditions. The values of Cmax (145.81 vs 176.27 vs 190.19 ng/mL), AUC0-t (1193.81 vs 1374.69 vs 1570.77 ng/mL*h) and (Cl 11.82 vs 14 .50 vs 13.01 mL/h) were lower for these individuals, respectively, but not statistically significant. Rivaroxaban prolonged PT values (17.80 vs 18.38 vs 18.62 s) and aPTT (45.90 vs 44.78 vs 47.00 s) when compared to baseline values, but without correlation with the studied variant. Rivaroxaban was well tolerated and no serious events were detected. Pharmacogenetic studies in healthy volunteers provide a lot of information about the influence of genetic polymorphisms on pharmacokinetics, biological effect and gives information on safety. The information collected can be used in the development of personalized medicine.