Evaluation of the Effect of Ticagrelor Dose Interruption and Treatment Resumption with or without Bolus Doses Through Population PK/PD Simulation.

Abstract

Background: Ticagrelor is an oral P2Y₁₂ receptor antagonist used mostly in combination with aspirin, in patients with acute coronary syndromes (ACS). Ticagrelor is discontinued 3-5 days before major procedures. Due to its reversible effect, discontinuation is likely to increase the risk of thrombosis. While the effect of dose interruptions on the risk of thrombosis has not been directly studied, pharmacokinetic/pharmacodynamic (PK/PD) simulations provide useful insights.

Objectives: The objective of the current study was to simulate the impact of therapy interruption on the PK/PD of ticagrelor.

Methods: The oral absorption of ticagrelor was described by a transit compartment model, and population PK/PD parameters were obtained from published literature. The PD of ticagrelor was described using a sigmoidal direct-response I_max model. A population PK/PD model describing the relationship between ticagrelor dose, plasma concentrations, and P2Y₁₂ reaction units (PRU) was used to perform simulations using Simulx (Lixoft, France). Simulated patients (n = 1000) received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily orally for 15-days. Doses were stopped on day 8 for 0-5 days and resumed with or without a loading dose.

Results: During uninterrupted ticagrelor use, median PRUs ranged between ~ 13 to ~ 40, with > 70% below low platelet reactivity (LPR). The % of PRUs below high platelet reactivity (HPR) drops to ~ 47%, ~ 11%, ~ 2% and 0% upon dose interruption of 1, 2, 3, and 5 days, respectively. Within 2 h of dose resumption with either the loading or the maintenance dose, > 94% of PRUs were below LPR.

Conclusion: Our results suggest the need for individualizing duration of dose interruption prior to surgery and its resumption afterwards.