Predicted effect of ticagrelor on the pharmacokinetics of dabigatran etexilate using physiologically based pharmacokinetic modeling

Dabigatran etexilate (DABE) is a direct oral anticoagulant (DOAC) and may be combined with ticagrelor, a P2Y(12) inhibitor with antiplatelet effects. This combination of antiplatelet drugs and anticoagulants would increases the risk of bleeding in patients. In addition, the potential drug interaction may further increase the risk of bleeding. At present, there is scarce research to clarify the results of the interaction between the two. Therefore, we conducted this study to identify the potential impact of ticagrelor on the pharmacokinetics of DABE using physiologically based pharmacokinetic (PBPK) modeling. The models reasonably predicted the concentration-time profiles of dabigatran (DAB), the transformation form after DABE absorption, and ticagrelor. For pharmacokinetic drug-drug interaction (DDI), exposure to DAB at steady state was increased when co-administrated with ticagrelor. The C(max) and AUC(0-t) of DAB were raised by approximately 8.7% and 7.1%, respectively. Meanwhile, a stable-state ticagrelor co-administration at 400 mg once-daily increased the C(max) and AUC(0-t) of DAB by approximately 12.8% and 18.8%, respectively. As conclusions, Ticagrelor slightly increased the exposure of DAB. It is possible to safely use ticagrelor in a double or triple antithrombotic regimen containing DABE, only considering the antithrombotic efficacy, but not need to pay much attention on the pharmacokinetic DDI.