Effects of Bojungikgitang, Ijintang, and Cheongsanggyeontongtang on the pharmacokinetics and pharmacodynamics of edoxaban

초록

Purpose Bojungikgitang (BJIGT), Ijintang (IJT), and Cheongsanggyeontongtang (CSGTT) are traditional herbal formulations with a long history of use in East Asian traditional medicine for the symptomatic management of cardiovascular and cerebrovascular diseases. Although these formulations are frequently coadministered with anticoagulants, clinical evidence on their interactions with direct oral anticoagulants (DOAC) remains scarce. This study aimed to evaluate the effects of BJIGT, IJT, and CSGTT on the pharmacokinetics and pharmacodynamics of edoxaban, a widely used DOAC. Methods In a fixed-sequence, two-period clinical study, healthy volunteers received 60 mg edoxaban alone and after repeated dosing with BJIGT, IJT, or CSGTT. Plasma concentrations of edoxaban and its active metabolite M4 were quantified by liquid chromatography coupled with tandem mass spectrometry. Pharmacokinetic parameters were compared using linear mixed-effects models. Pharmacodynamic effects were assessed with prothrombin time and activated partial thromboplastin time. The CYP3A4 inhibitory potential of BJIGT, IJT, and CSGTT was evaluated in vitro.Results BJIGT significantly increased edoxaban exposure, approximately doubling systemic levels, whereas IJT exerted minimal effects and CSGTT reduced exposure by approximately 40%. Similar directional changes were observed for M4. Despite substantial pharmacokinetic alterations, no significant changes in pharmacodynamics were detected. CYP3A4 inhibition was negligible with BJIGT and IJT and weak with CSGTT. Conclusion BJIGT and CSGTT produced meaningful changes in edoxaban exposure, comparable to the established interactions of edoxaban with strong P-glycoprotein inhibitors and inducers. Despite unchanged pharmacodynamic endpoints, these findings suggest that clinical consideration is warranted in patients receiving edoxaban in combination with BJIGT or CSGTT.

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