Key result
Simulated carbamazepine co-administration cuts rivaroxaban exposure by ~69%.
Why the study?
Rivaroxaban is a substrate of CYP enzymes and Pgp/BCRP transporters, while carbamazepine is a strong inducer, leading to an expected drug-drug interaction that required prediction in humans.
Does co-administration of carbamazepine reduce the pharmacokinetic exposure of rivaroxaban in humans?
Does co-administration of carbamazepine reduce the pharmacokinetic exposure of rivaroxaban in humans?
Pharmacokinetic modeling suggests carbamazepine significantly reduces rivaroxaban exposure, warranting caution with co-administration.
Answers are grounded in this paper and cite their sources.
May warrant caution with co-administration; leaves open confirmation in human pharmacokinetic studies.
Rivaroxaban (RIV) is one of the direct oral anticoagulants used to prevent and treat venous and arterial thromboembolic events. Considering the therapeutic indications, RIV is likely to be concomitantly administered with various other drugs. Among these is carbamazepine (CBZ), one of the recommended first-line options to control seizures and epilepsy. RIV is a strong substrate of cytochrome P450 (CYP) enzymes and Pgp/BCRP efflux transporters. Meanwhile, CBZ is well known as a strong inducer of these enzymes and transporters. Therefore, drug–drug interaction (DDI) between CBZ and RIV is expected. This study aimed to predict the DDI profile of CBZ and RIV in humans by using a population pharmacokinetics (PK) model-based approach. We previously investigated the population PK parameters of RIV administered alone or with CBZ in rats. In this study, those parameters were extrapolated from rats to humans by using simple allometry and liver blood flow scaling, and then applied to back-simulate the PK profiles of RIV in humans (20 mg RIV per day) used alone or with CBZ (900 mg CBZ per day). Results showed that CBZ significantly reduced RIV exposure. The AUCinf and Cmax of RIV decreased by 52.3% and 41.0%, respectively, following the first RIV dose, and by 68.5% and 49.8% at the steady state. Therefore, the co-administration of CBZ and RIV warrants caution. Further studies investigating the extent of DDIs between these drugs should be conducted in humans to fully understand their safety and effects.
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Ngo et al. (2023) studied Drug-drug interaction. Carbamazepine co-administered with Rivaroxaban vs. Rivaroxaban alone (20 mg per day) was evaluated on Pharmacokinetic profiles (AUCinf and Cmax of rivaroxaban) (68.5% decrease in AUCinf and 49.8% decrease in Cmax at steady state). Simulated co-administration of carbamazepine significantly reduced rivaroxaban exposure, decreasing steady-state AUCinf by 68.5% and Cmax by 49.8%.
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