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

Autor: Dominick J. Angiolillo, Paul A. Gurbel, Marc P. Bonaca, Anders Himmelmann, Magnus Åstrand, Carl Amilon, Daniel Röshammar, Robert F. Storey, Bengt Hamrén
Rok vydání: 2018
Předmět:
Male
Ticagrelor
Platelet Aggregation
Myocardial Infarction
Coronary Artery Disease
030226 pharmacology & pharmacy
Coronary artery disease
0302 clinical medicine
Multicenter Studies as Topic
Medicine
Pharmacology (medical)
Platelet
030212 general & internal medicine
Myocardial infarction
pharmacokinetic
NONMEM
Randomized Controlled Trials as Topic
Aged
80 and over
education.field_of_study
Middle Aged
Clopidogrel
Treatment Outcome
Cardiology
Female
Original Article
medicine.drug
Adult
Blood Platelets
medicine.medical_specialty
Platelet Function Tests
Population
Placebo
Models
Biological
inhibition of platelet aggregation
Drug Administration Schedule
Young Adult
03 medical and health sciences
Clinical Trials
Phase II as Topic
Internal medicine
Humans
education
Aged
Pharmacology
Dose-Response Relationship
Drug
business.industry
Original Articles
medicine.disease
pharmacodynamic
Clinical Trials
Phase III as Topic
Pharmacodynamics
Purinergic P2Y Receptor Antagonists
business
Zdroj: British Journal of Clinical Pharmacology
ISSN: 1365-2125
0306-5251
Popis: AIM: 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 non-linear 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 and pharmacodynamic (PK/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. 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 modeled doses below 60mg, the response is overall reduced, more variable between patients, and patients will display greater peak-to-trough variability.
Databáze: OpenAIRE
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