(P048) A SIMPLE DOSING RULE TO IMPROVE EFFICACY AND SAFETY OF TICAGRELOR

Background: Ticagrelor, a potent reversible inhibitor of the P2Y12 receptor, is widely used to prevent thrombotic events in patients undergoing stent placement. Despite its clinical benefits, variability in patient pharmacokinetics leads to important variability in drug concentration, safety and efficacy. Current fixed-dosing strategies often result in over-suppression of platelet reactivity, quantified by Platelet Reactivity Units (PRU), elevating the risk of bleeding complications. A personalized approach to ticagrelor dosing has the potential to significantly enhance patient outcomes by optimizing concentration to the therapeutic window.

METHODS AND RESULTS: Using (e)-Campsis software to study a pharmacokinetic-pharmacodynamic (PK-PD) model, we simulated the impact of various ticagrelor dosing strategies (90 mg bid, 60 mg bid, 30 mg bid) tailored to individual patient PRU levels in a virtual population of 1,000 patients. This model targeted a therapeutic PRU range of 85-180 to maximize efficacy while minimizing bleeding risks. Optimal dosing recommendations were derived using steady-state PRU measurements. A decision tree analysis facilitated personalized dosing adjustments, which were validated against a fixed-dose regimen of 60 mg bid in a secondary cohort of 2,500 virtual patients.

Analysis revealed that personalized dosing significantly reduced the number of patients experiencing sub-optimal PRU levels—either too low, increasing bleeding risk, or too high, reducing anti-thrombotic efficacy. The model predicted that with the standard-dose, fixed 60-mg bid regimen, the 5% of the population developing the highest drug exposure would have an 80% chance of being over-suppressed (PRU < 10), therefore a high risk of bleeding. An adjusted dosing strategy, reduced this chance to 50%, reducing bleeding risk without affecting the number of patients with highly effective platelet suppression at PRU below 90. Both dosing regimens maintained PRU below 180 in the whole population, throughout treatment, indicating sufficient platelet suppression, while providing the opportunity to address the small number of patients experiencing insufficient suppression of PRU levels, by increasing their dose to reduce the risk of thrombotic events.

Conclusion: Our findings support further investigation of the use of a personalized ticagrelor dosing framework, that can be guided by clinically available PRU measurement techniques to easily adjust dosing to better fit the patient's pharmacokinetics. Such a strategy aligns with current trends toward precision medicine to greatly improve the balance of efficacy and safety for patients undergoing stent implantation. Clinical trials of such personalized strategies could potentially revolutionize the standard of care in ischemic cardiovascular patients, reducing bleeding complications while ensuring effective anti-thrombotic protection.