Pharmacokinetic Modeling of Ticagrelor and Ticagrelor Active Metabolite Removal by the DrugSorb-ATR Device in a Randomized Controlled Study of Patients Undergoing Cardiac Surgery

Excessive surgical bleeding is a potential risk in patients taking ticagrelor who must undergo urgent cardiothoracic (CT) surgery before adequate washout of the drug can occur. The DrugSorb-Antithrombotic removal (ATR) device is a polymer sorbent-filled hemoadsorption cartridge that can remove unbound (active) fractions of ticagrelor and ticagrelor active metabolite (TAM) from blood. STAR-T was a randomized double-blind sham-controlled clinical trial investigating whether the intraoperative use of the device could reduce perioperative bleeding complications in patients undergoing CT surgery within 2 days of ticagrelor discontinuation. Blood samples were collected during the study for total drug level measurements because the ability to measure unbound ticagrelor and TAM (0.2% of total levels) requires an ultra-high sensitivity assay, which is not commercially available. A published and validated pharmacokinetic (PK) model was used to explore the effect of the device on unbound ticagrelor/TAM using the total drug concentrations from the study. The model performed well for simulations of total ticagrelor and TAM, which indicated that the unbound concentrations were also appropriate. The model demonstrated that DrugSorb-ATR significantly reduced unbound ticagrelor and TAM concentrations. Linear and logistic regression analyses of summed ticagrelor and TAM concentrations showed that the DrugSorb-ATR device reduced the probability of clinically relevant bleeding in STAR-T because of the reduction in unbound ticagrelor and TAM.