Predicting drug-drug interactions and optimal dosing of betrixaban with physiologically based pharmacokinetic modeling in patients with renal impairment who were coadministered with P-glycoprotein inhibitors.

ObjectiveTo optimize dosing adjustments in patients with renal impairment who were coadministered with P-glycoprotein inhibitors-verapamil or amiodarone-using a physiologically based pharmacokinetic model.MethodsThe developed physiologically based pharmacokinetic model was corroborated using previously reported pharmacokinetic parameters across multiple doses, ratio values in drug-drug interactions, and pharmacokinetic ratio values in patients with renal impairment.ResultsThe physiologically based pharmacokinetic model exhibited fold errors between 0.7 and 1.3 and effectively illustrated changes in pharmacokinetic ratios in patients with renal impairment. The model suggested that the dosing regimen of betrixaban should be reduced to 40 mg once daily in patients with mild renal impairment who were administered with verapamil or amiodarone. Additionally, it is advised that the dosing regimen of betrixaban be reduced to 40 mg once daily in patients with moderate renal impairment who were administered with amiodarone, whereas no suitable dosing is recommended for those administered with verapamil. For patients with severe renal impairment, it may be reasonable to avoid concurrent use of betrixaban with P-glycoprotein inhibitors.ConclusionsThe coadministration of P-glycoprotein inhibitors elevates the exposure of betrixaban and may heighten the risk of major bleeding. Reduced dosing regimens are recommended for patients with renal impairment when betrixaban is coadministered with P-glycoprotein inhibitors.