Handling delayed or missed direct oral anticoagulant doses: model-informed individual remedial dosing

Abstract

Non-adherence to direct oral anticoagulants (DOACs) pharmacotherapy may increase the risks of thromboembolism or bleeding, and delayed or missed doses are the most common types of non-adherence. Current recommendations from regulatory agencies or guidelines regarding this issue lack evidence and fail to consider individual differences. The study aims to develop individual remedial dosing strategies when the dose was delayed or missed for DOACs including rivaroxaban, apixaban, edoxaban, and dabigatran etexilate. Remedial dosing regimens based on population pharmacokinetic (PK)-pharmacodynamic (PD) modeling and simulation strategies were developed to expeditiously restore drug concentration or PD biomarkers within the therapeutic range. Population PK-PD characteristics of DOACs were retrieved from previously published literature. The effect of factors which influence PK and PD parameters were assessed for their impact on remedial dosing regimens. A web-based dashboard was established with R-shiny to recommend remedial dosing regimens based on patient traits, dosing schedules, and delay duration. Addressing delayed or missed doses relies on the delay time and specific DOACs involved. Additionally, age, body weight, renal function, and polypharmacy may marginally impact remedial strategies. The proposed remedial dosing strategies surpass current recommendations, with less deviation time beyond the therapeutic range. The online dashboard offers quick and convenient solutions for addressing missed or delayed DOACs. We developed a superior, cost-free tool for managing delayed or missed DOACs doses. Individualized remedial dosing strategies could be approached based on patient characteristics to decrease the risks of bleeding and thrombosis.