Integrated Pharmacokinetics/Pharmacodynamics Model and Simulation of the Ticagrelor Effect on Patients with Acute Coronary Syndrome

Abstract

BackgroundData available for pharmacokinetics (PK)/pharmacodynamics (PD) of ticagrelor and significant endogenous/exogenous factors or biomarkers related to bleeding events in both healthy and clinical patients are limited.ObjectiveBased on PK and PD data from multicenter healthy subjects and patients, we aimed to establish an integrated approach towards population PK (pop PK) and the PD model of ticagrelor.MethodsThis study was conducted as a multicenter, prospective clinical registration study involving both healthy subjects and clinical patients. The integrated Pharmacokinetic/pharmacodynamic (PK/PD) models were characterized based on PK/PD [ticagrelor concentration, aggregation baseline (BASE), P2Y12 response unit (PRU) and inhibition rate (INHIBIT)] data from 175 healthy volunteers. The model was corrected by sparse PD (BASE, PRU and INHIBIT) data from 208 patients with acute coronary syndrome (ACS). The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored.ResultsA one-compartment, linear model with first-order absorption was adopted as PK model. Food status (FOOD) and body weight (WT) significantly influenced clearance and improved the fitting degree of the PK model, while SEX was selected as the covariates of the PD model. For patients taking ticagrelor 90 mg, the peak value [mean (95% CI)] of PRU was 355.15 (344.24-366.06) and the trough value was 3.64 (3.14-4.15). The PRU mean parameters were basically within the expected range (80-200) of the literature suggestions.ConclusionA fixed dose of ticagrelor, without adjusting the dosing regimen other than covariates of FOOD/WT/SEX, could be used in patients with acute coronary syndromes, and the standard regimen could be used in Chinese patients from the perspective of exposure.