Effects of Carbamazepine and Phenytoin on Pharmacokinetics and Pharmacodynamics of Rivaroxaban

Abstract

Rivaroxaban (RIV) is commonly prescribed with carbamazepine or phenytoin (CBZ/PHT) in post-stroke seizure or post-stroke epilepsy patients. Although adverse events have been reported in several previous studies when they are coadministered, there are no studies of the interactions between these drugs. Therefore, our study was conducted to solve this lack of information. The potential effects of CBZ/PHT were investigated by comparing the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of RIV between the control group (RIV alone) and the test groups (RIV administered with CBZ/PHT) in rats using the noncompartmental analysis (NCA) and the compartmental model approach. The NCA results indicate that AUCt of RIV decreased by 57.9% or 89.7% and Cmax of RIV decreased by 43.3% or 70.0% after administration of CBZ/PHT, respectively. In addition, both CBZ and PHT generally reduced the effects of RIV on the prothrombin times of the blood samples. PK profiles of RIV were most properly described by a two-compartment disposition model with a mixed first- and zero-order absorption kinetics and a first-order elimination kinetics. The compartmental model approach showed that a 211% or 1030% increase in CL/F of RIV and a 33.9% or 43.4% increase in D2 of RIV were observed in the test groups by the effects of CBZ/PHT, respectively. In conclusion, CBZ and PHT significantly reduced RIV exposure and therefore reduced the therapeutic effects of RIV. Consequently, this might result in adverse events due to insufficient RIV concentration to attain its therapeutic effects. Further studies are needed to validate this finding.

Application of the Population Pharmacokinetics Model-Based Approach to the Prediction of Drug–Drug Interaction between Rivaroxaban and Carbamazepine in Humans

“…In this study, it was well known that RIV is a substrate of Pgp/BCRP and CBZ an inducer of these transporters [ 20 , 21 , 39 ]. Further, the role of the Pgp induction effect in the DDI of RIV was supported by the results of the investigation conducted in rats [ 24 ]. In addition to the increased plasma clearance, CBZ also reduced the absorption rate of RIV by extension of the absorption time of the zero-order absorption process (from 6.62 to 8.86 h), which described the movement of the drug from the GI tract, crossing the basolateral membrane, and entering the systemic circulation via the capillary network surrounding the enterocytes and hepatic portal vein.…”

“…Within the scope of this study, we solely describe the parts related to the effects of CBZ. The PK study design and results are described in detail in our previous study [ 24 ]. Figure 1 shows the plasma concentration versus the time of RIV, demonstrating that CBZ significantly reduced the exposure of RIV.…”

“…The effect of pretreatment with CBZ as a covariate factor in the RIV PK was also investigated. Schematic representation of the PopPK model and the effect of CBZ on the PK of RIV are described in detail in our previous study [ 24 ] and illustrated in Figure 2 . The final parameters estimates, their relative standard errors, and random errors are listed in Table 1 .…”

“…Because of a lack of in vitro and in vivo experiments concerning the reaction, the Pgp transporter-mediated induction effect was not implemented in the developed CBZ model. As a result, the decreases in the PK parameters of RIV due to CBZ effects might have been under-predicted, while all possible (known and unknown) effects of CBZ were considered in the PopPK approach based on a real study conducted in rats [ 24 ]. This is a common limitation of the PBPK models.…”

“…Results of our PBPK model-based approach showed that CBZ significantly reduces the exposure of RIV by 35.2% after the first RIV dose (AUC decreased from 2221.3 to 1438.7 ng · h/mL). In addition, our group recently conducted another study to investigate the DDI profile of RIV and CBZ in rats [ 24 ], indicating a decrease of 57.9% in RIV AUC due to pretreatment with CBZ. Using the PopPK model-based approach to predict the DDI profiles of RIV when used concomitantly with CBZ in humans was the aim of this study.…”