Affiliation:
1. College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
2. Department of Bio-AI Convergence, Chungnam National University, Daejeon 34134, Republic of Korea
Abstract
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.
Funder
Chungnam National University
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine
Reference52 articles.
1. The Mechanism of Action of Rivaroxaban—An Oral, Direct Factor Xa Inhibitor—Compared with Other Anticoagulants;Samama;Thromb. Res.,2011
2. Bayer Pharma AG (2013). Xarelto (Rivaroxaban) Summary of Product Characteristics, Bayer Pharma AG.
3. European Medicines Agency (2008). CHMP Assessment Report for Xarelto, European Medicines Agency.
4. Clinical Pharmacokinetic and Pharmacodynamic Profile of Rivaroxaban;Mueck;Clin. Pharmacokinet.,2014
5. Co-Administration of Rivaroxaban with Drugs That Share Its Elimination Pathways: Pharmacokinetic Effects in Healthy Subjects;Mueck;Br. J. Clin. Pharmacol.,2013