Pharmacokinetic–pharmacodynamic modelling of platelet response to ticagrelor in stable coronary artery disease and prior myocardial infarction patients

• Published in: British journal of clinical pharmacology Vol. 85; no. 2; pp. 413 - 421
• Main Authors: Åstrand, Magnus, Amilon, Carl, Röshammar, Daniel, Himmelmann, Anders, Angiolillo, Dominick J., Storey, Robert F., Gurbel, Paul A., Bonaca, Marc P., Hamrén, Bengt
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.02.2019
• Subjects: Adult; Aged; Aged, 80 and over; Blood Platelets - drug effects; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Coronary Artery Disease - blood; Coronary Artery Disease - drug therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; inhibition of platelet aggregation; Male; Middle Aged; Models, Biological; Multicenter Studies as Topic; Myocardial Infarction - blood; Myocardial Infarction - prevention & control; NONMEM; Original; pharmacodynamic; pharmacokinetic; Platelet Aggregation - drug effects; Platelet Function Tests; Purinergic P2Y Receptor Antagonists - pharmacology; Purinergic P2Y Receptor Antagonists - therapeutic use; Randomized Controlled Trials as Topic; ticagrelor; Ticagrelor - pharmacology; Ticagrelor - therapeutic use; Treatment Outcome; Young Adult; pharmacodynamic; ticagrelor; inhibition of platelet aggregation; pharmacokinetic; NONMEM
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13812

Aims To characterize ticagrelor exposure‐response relationship for platelet inhibition in patients with stable coronary artery disease (CAD) and a history of myocardial infarction (MI), using nonlinear mixed effects modelling and simulation. Methods Platelet function data were integrated with plasma concentration data of ticagrelor and its active metabolite AR‐C1249010XX in a population pharmacokinetic (PK) and pharmacodynamic (PD) model, based on two clinical studies. In the ONSET/OFFSET study, PK and platelet function were assessed in 123 CAD patients receiving placebo, ticagrelor (180 mg followed by 90 mg twice daily) or clopidogrel (600 mg followed by 75 mg once daily). In the PEGASUS‐TIMI 54 platelet function substudy, PK and platelet function were assessed during maintenance dosing in 180 prior MI patients receiving placebo, ticagrelor 60 mg or ticagrelor 90 mg twice daily. Results Platelet inhibition by ticagrelor was described by a sigmoidal Emax model. On average, half maximal inhibition was reached at ticagrelor concentrations of 116 (RSE: 5.3%) nmol l–1. Simulations showed that near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At simulated lower doses, platelet inhibition is overall reduced, more variable between patients, and show greater peak‐to‐trough variability. Ticagrelor antiplatelet response was similar between the studied patient populations. Conclusions In patients with stable CAD or a history of MI, near maximal platelet inhibition is achieved with both ticagrelor 60 and 90 mg twice daily. At modelled doses <60 mg, the response is reduced overall, more variable between patients, and patients will display greater peak‐to‐trough variability.