Article Figures & Data
Additional Files
Data Supplement
- Supplemental Data -
Supplementary Methods
Supplementary Table 1 - Clearance parameters of rivaroxaban utilized for retrograde analysis within the Simcyp simulator.
Supplementary Table 2.1 - Key input parameters for the PBPK model of verapamil.
Supplementary Table 2.2 - Key input parameters for the PBPK model of norverapamil.
Supplementary Table 2.3 - Key input parameters for the PBPK model of ketoconazole.
Supplementary Table 3 - Details of clinical study designs for PBPK model verification.
Supplementary Table 4 - Serum creatinine input for mild renal impaired population.
Supplementary Table 5 - Non-specific binding of rivaroxaban and ketoconazole to ultrafiltration apparatus, culture media and cell homogenate.
Supplementary Table 6 - Comparison of PK parameters between simulated and observed data for model verification of verapamil and norverapamil.
Supplementary Table 7 - Comparison between Simcyp and experimental inhibitory parameters.
Supplementary Table 8 - Comparison of (A) clinically observed renal clearance with simulated renal clearances of rivaroxaban using the (B) 35-compartment mechanistic kidney model versus (C) MechKiM module within the Simcyp simulator.
Supplementary Table 9 - Physiological changes in renal impairment.
Supplementary References.
Supplementary Figure 1 - In vitro in vivo correlation workflow to recapitulate the PK of a controlled release formulation of verapamil.
Supplementary Figure 2 - Investigation of the P-gp-mediated transport kinetics of rivaroxaban.
Supplementary Figure 3 - Investigation of the hOAT-mediated uptake transport kinetics of rivaroxaban.
Supplementary Figure 4 - Top-down optimization of the OAT3-mediated basolateral uptake of rivaroxaban.
Supplementary Figure 5 - MBI of CYP3A4 and CYP2J2-mediated metabolism of rivaroxaban by verapamil and norverapamil.
Supplementary Figure 6 - Reversible inhibition of CYP3A4 and CYP2J2-mediated metabolism of rivaroxaban by verapamil and norverapamil.
Supplementary Figure. 7 - Inhibition of the enzyme and transporter-mediated elimination of rivaroxaban by ketoconazole and verapamil.
Supplementary Figure 8 - (A) Simulated rivaroxaban AUC ratio at different input values of OAT3 Ki and P-gp Ki. (B) Simulated rivaroxaban CLR at different input values of OAT3 CLint,T and P-gp REF.
- Supplemental Modelling Data 1 -
Supplementary Modelling Data File 1 - Simulated PK of rivaroxaban in mild renal impairment.
- Supplemental Modelling Data 2 -
Supplementary Modelling Data File 2 - Predicted extent of DDI between rivaroxaban and verapamil in a healthy population.
- Supplemental Modelling Data 3 -
Supplementary Modelling Data File 3 - Predicted magnitude of DDI between ketoconazole and rivaroxaban in a healthy population where the Ki of ketoconazole against OAT3-mediated rivaroxaban uptake has been optimized.
- Supplemental Modelling Data 4 -
Supplementary Modelling Data File 4 - Simulated PK of rivaroxaban in the absence of mechanistic kidney modelling.
- Supplemental Modelling Data 5 -
Supplementary Modelling Data File 5 - Simulated PK of rivaroxaban in the presence of mechanistic kidney modelling.
- Supplemental Data -