Variability of Rivaroxaban Pharmacokinetics and its Genetic Predictors

Warfarin has been a widely used oral anticoagulant for a long time. It is associated with large inter-patients? variability in its pharmacokinetics and regular therapeutic drug monitoring is required. The impact of genetic factors on the pharmacokinetics of warfarin has been well established. New Oral Anti-Coagulants (NOACs) have recently been introduced and increasing used. Their pharmacokinetics are more expected than warfarin and they have less interactions with other drugs and food. They don?t require monitoring and have fixed dosing regimen. With the increasing use of these drugs, it is becoming evident that there is more variability in their pharmacokinetics than what was initially expected. As seen with warfarin, it is likely that genetic polymorphisms play an important rule to explain this variability. There are limited number of studies that assessed the impact of the genetic polymorphisms on the pharmacokinetics of these agents and they are limited by the sample size, small number of studied loci and the inconsistencies in the results. Therefore, we aim to estimate the inter-individual pharmacokinetic variability of rivaroxaban, one of the commonly used NOAC, and to assess the impact of genetic polymorphisms on this variability in a Genome-Wide Association Study (GWAS) approach. We will include adult patients who are taking rivaroxaban for any indication. Patients will be recruited from Sultan Qaboos University Hospital, Royal Hospital, Armed Forces Hospital and Khoula Hospital. The following parameters will be calculated using a non-compartmental model: Area Under the Curve (AUC) [0,Inf; computed using Trapezoidal methods], peak plasma concentration (Cmax), time to Cmax (Tmax) and Coefficient of variation (CV%) for Cmax and AUC [0,inf]. Rivaroxaban concentrations will be measured using ultra high performance liquid chromatography with mass spectrometry. The anticoagulant activity of rivaroxaban will be measured using Anti-Xa assay. Affymetrix DNA microarray system will be used in this study to generate the genotypes. The AUC and C max will be compared using Linear mixed effect regression model. Sample size calculation is based on an additive genetic model with a modest effect size (R^2 of 10%) of the polymorphism and Bonferroni correction for multiple testing (An alpha threshold of 5*10^-8; One million SNP multiple testing) which is a two tailed p value. To get 80% power, we will require 397 patients. The study will help advance our understanding of the pharmacokinetics of rivaroxaban, estimate the magnitude of the variability and assess the impact of different genetic and non-genetic factors on its variability. If truly influential, these genetic and non-genetic factors can be used to predict patients with extreme pharmacokinetic parameters in whom a drug monitoring is required. Informed consent will be given to patients including all the information that will be fully confidential. It will be completely voluntary and the patients will have all the rights to refuse answering any question or stop at any time. Ethical approval will be obtained before conducting the study. It is a low risk study as the only risk in this study is this associated with venipuncture.