Predicting drug-drug interactions with physiologically based pharmacokinetic/pharmacodynamic modelling and optimal dosing of apixaban and rivaroxaban with dronedarone co-administration

• Published in: Thrombosis research Vol. 218; pp. 24 - 34
• Main Authors: Wen, Hai-Ni, He, Qing-Feng, Xiang, Xiao-Qiang, Jiao, Zheng, Yu, Jian-Guang
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.10.2022
• Subjects: Apixaban; Dronedarone; Drug-drug interaction; Major bleeding risk; Physiologically based pharmacokinetic; Rivaroxaban; eGFR; Cmax; FDA; Km; P-gp; AF; DOACs; CI; Vmax; PBPK/PD; Dronedarone; AUC; Rivaroxaban; ADAM; Physiologically based pharmacokinetic; DDIs; MBI; Apixaban; Major bleeding risk; Vss; CYP; Drug-drug interaction
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/j.thromres.2022.08.007

The concurrent administration of dronedarone and oral anti-coagulants is common because both are used in managing atrial fibrillation (AF). Dronedarone is a moderate inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme and P-glycoprotein (P-gp). Apixaban and rivaroxaban are P-gp and CYP3A4 substrates. This study aims to investigate the impact of exposure and bleeding risk of apixaban or rivaroxaban when co-administered with dronedarone using physiologically based pharmacokinetic/pharmacodynamic analysis. Modeling and simulation were conducted using Simcyp® Simulator. The parameters required for dronedarone modeling were collected from the literature. The developed dronedarone physiologically based pharmacokinetic (PBPK) model was verified using reported drug-drug interactions (DDIs) between dronedarone and CYP3A4 and P-gp substrates. The model was applied to evaluate the DDI potential of dronedarone on the exposure of apixaban 5 mg every 12 h or rivaroxaban 20 mg every 24 h in geriatric and renally impaired populations. DDIs precipitating major bleeding risks were assessed using exposure-response analyses derived from literature. The model accurately described the pharmacokinetics of orally administered dronedarone in healthy subjects and accurately predicted DDIs between dronedarone and four CYP3A4 and P-gp substrates with fold errors <1.5. Dronedarone co-administration led to a 1.29 (90 % confidence interval (CI): 1.14–1.50) to 1.31 (90 % CI: 1.12–1.46)-fold increase in the area under concentration-time curve for rivaroxaban and 1.33 (90 % CI: 1.15–1.68) to 1.46 (90 % CI: 1.24–1.92)-fold increase for apixaban. The PD model indicated that dronedarone co-administration might potentiate the mean major bleeding risk of apixaban with a 1.45 to 1.95-fold increase. However, the mean major bleeding risk of rivaroxaban was increased by <1.5-fold in patients with normal or impaired renal function. Dronedarone co-administration increased the exposure of rivaroxaban and apixaban and might potentiate major bleeding risks. Reduced apixaban and rivaroxaban dosing regimens are recommended when dronedarone is co-administered to patients with AF.