A pooled population pharmacokinetic analysis of ticagrelor in acute coronary syndrome using simulated data

Ticagrelor is a P2Y12 inhibitor used to reduce thrombotic events in acute coronary syndrome (ACS). Optimal dosing is crucial for preventing bleeding and thrombosis; therefore, we developed the population pharmacokinetics (PK) of ticagrelor by incorporating results from previous population PK studies. Studies were identified through a PubMed search, and an integrated PK model was developed using pooled synthetic datasets. Two published PK models generated virtual cohorts of 1,000 individuals each with covariates of age, sex, weight, and smoking status. A one-compartment model with a parent-metabolite relationship was used to describe ticagrelor and its active metabolite. The final model estimated ticagrelor Ka at 0.613 h⁻¹, oral clearance (CL/F) at 13.3 L/h and apparent volume of distribution (Vd/F) of 228 L; the metabolite showed oral clearance (CLM/F) of 9.75 L/h and apparent volume of distribution (VM/F) of 4.59 L. Simulations showed that elderly patients and smokers receiving 90 mg twice-daily frequently exceeded the upper safety threshold (Cmin, ss > 360 ng/mL), whereas a 60 mg twice-daily regimen maintained exposure within the target therapeutic range (180-360 ng/mL). These hypothesis-generating findings warrant prospective validation in diverse ACS populations.