Rivaroxaban is an oral anticoagulant which acts by inhibiting factor Xa of the coagulation network. It is used in the prevention and treatment of thromboembolism in patients undergoing knee or hip replacement surgery and in stroke prevention in patients with atrial fibrillation. Rivaroxaban undergoes CYP-mediated oxidative metabolism mainly via CYP3A4 with a minor contribution of CYP2J2. It is also a substrate for efflux transporter P-gp and uptake transporter OAT3 in kidney. The aim of this work was to develop a physiologically based pharmacokinetic (PBPK) model of rivaroxaban and explore the role of OAT3 transporter in its renal excretion.
The in vitro Km of CYP3A4 (5.78µM) was converted to in vivo Km using metabolism and transporter module of GastroPlus which resulted in in vivo Km of 0.128 mg/L, similarly in vitro Km of OAT3 (1.1 µM) resulted in in vivo Km of 0.022 mg/L, Km of P-gp was fixed as 10 mg/L and Vmax for all enzymes and transporters was fitted. Simulated plasma concentration-time profiles of rivaroxaban using the kinetic parameters were in close agreement with observed data across different dose levels, PK parameters are shown in Table 1 for different doses, Figure 1 shows plasma concentration profiles of rivaroxaban for 10 mg and 20 mg doses in Caucasian and Chinese subjects. The validated final model was able to capture the urinary excretion data accurately and confirm the role of OAT3 and P-gp in urinary excretion of rivaroxaban.
The absorption and pharmacokinetics of rivaroxaban in healthy subjects were modeled using in vitro and in silico data describing the drug’s physicochemical and biopharmaceutical properties, along with in vitro kinetics of CYP3A4, OAT3 and estimated kinetics of P-gp. The model was successfully applied to capture the gut and liver metabolism of rivaroxaban by CYP3A4, and renal elimination mediated by P-gp and OAT3 transporters. Chinese population showed slightly lower total clearance of rivaroxaban than the Caucasian population. The differences in PK between these two populations could be explained by 1) lower expression levels of CYP3A4 and 2) lower expression levels of OAT3 in Chinese populations .
 Y. Tsuruya, T. Nakanishi, H. Komori, X. Wang, N. Ishiguro, T. Kito, K. Ikukawa, W. Kishimoto, S. Ito, O. Schaefer, T. Ebner, N. Yamamura, H. Kusuhara, I. Tamai, Different Involvement of OAT in Renal Disposition of Oral Anticoagulants Rivaroxaban, Dabigatran, and Apixaban, Journal of pharmaceutical sciences, 106 (2017) 2524-2534.
 S.W. Yee, A.N. Nguyen, C. Brown, R.M. Savic, Y. Zhang, R.A. Castro, C.D. Cropp, J.H. Choi, D. Singh, H. Tahara, S.L. Stocker, Y. Huang, C.M. Brett, K.M. Giacomini, Reduced renal clearance of cefotaxime in Asians with a low-frequency polymorphism of OAT3 (SLC22A8), Journal of pharmaceutical sciences, 102 (2013) 3451-3457.
 C. Balram, A. Sharma, C. Sivathasan, E.J. Lee, Frequency of C3435T single nucleotide MDR1 genetic polymorphism in an Asian population: phenotypic-genotypic correlates, British journal of clinical pharmacology, 56 (2003) 78-83.