Comparative Pharmacokinetics and Pharmacodynamics of Platelet Adenosine Diphosphate Receptor Antagonists and their Clinical Implications

Abstract

Over the last two decades or more, anti-platelet therapy has become established as a cornerstone in the treatment of patients with ischaemic cardiovascular disease, since such drugs effectively reduce arterial thrombotic events. The original agent used in this context was aspirin (acetylsalicylic acid) but, with the advent of adenosine diphosphate (ADP) receptor antagonists, the use of dual anti-platelet therapy has resulted in further improvement in cardiovascular outcomes when compared with aspirin alone. The first group of platelet ADP receptor antagonists to be developed was the thienopyridine class, which comprise inactive pro-drugs that require in vivo metabolism to their active metabolites before exerting their inhibitory effect on the P2Y(12) receptor. Clopidogrel has been the principal ADP receptor antagonist in use over the past decade, but is limited by variability in its in vivo inhibition of platelet aggregation (IPA). The pharmacokinetics of clopidogrel are unpredictable due to their vulnerability to multiple independent factors including genetic polymorphisms. Expression of the 3435T/T genetic variant encoding the MDR1 gene for the P-glycoprotein efflux transporter results in a significantly reduced maximum drug concentration and area under the plasma concentration-time curve as intestinal absorption of clopidogrel is reduced; and the expression of the mutant *2 allele of CYP2C19 results in similar pharmacokinetic effects as the two cytochrome P450 (CYP)-mediated steps required for the production of the active metabolite of clopidogrel are impaired. These variable pharmacokinetics lead to erratic pharmacodynamics and cannot reliably be overcome with increased dosing. Both prasugrel, a third-generation thienopyridine, and ticagrelor, a cyto-pentyl-triazolo-pyrimidine, have more predictable pharmacokinetics and enhanced pharmacodynamics than clopidogrel. Neither appears to be affected by the same genetic polymorphisms as clopidogrel; prasugrel requires only a single CYP-mediated step to produce its active metabolite and ticagrelor is not a pro-drug. Enhanced IPA by both prasugrel and ticagrelor is achieved at the expense of increased major bleeding, although this is partially mitigated in the case of ticagrelor due to its reversible IPA. However, the reversible binding of ticagrelor to the P2Y(12) receptor requires a twice-daily dosing regimen. Due to limited data from clinical studies, the use of prasugrel is currently restricted to individuals undergoing percutaneous coronary intervention who are ≤75 years old and have a body weight ≥60 kg. The clinical data for ticagrelor are more comprehensive and this drug therefore has a place in the management of patients with acute coronary syndrome at moderate-to-high risk of ischaemic events, irrespective of treatment strategy. Here we review in detail the pharmacokinetics and pharmacodynamics of clopidogrel, prasugrel and ticagrelor, and explore the implications of the differences in these parameters for their clinical use.

In-Hospital Switching Between Clopidogrel and Prasugrel Among Patients With Acute Myocardial Infarction Treated With Percutaneous Coronary Intervention

“…3,4 However, these agents are associated with higher risk of bleeding; are more costly; and differ in side effect profiles, drug interactions, contraindications, precautions for use, and dosing regimen. 5 When initiating ADP receptor inhibitors early during hospitalization for MI, information about the risk of recurrent thrombotic events, bleeding, patient adherence to medication, and affordability of drug may not be known. Given availability of several ADP receptor inhibitors, optimizing such factors during hospitalization by switching drug regimen may be a consideration for some patients.…”

Pharmacogenetics and Cardiovascular Disease—Implications for Personalized Medicine

“…The first activation step is thought to be mediated largely by CYP2C19, CYP1A2, and CYP2B6, generating the intermediate metabolite 2-oxo-clopidogrel. This is followed by metabolism to the active metabolite, for which CYP3A, CYP2C19, CYP2B6, and CYP2C9 are involved (Kazui et al, 2010;Sangkuhl et al, 2010;Floyd et al, 2012). Genetic studies suggested a role for paroxonase 1 in the metabolic activation, but more recent studies have called this into question (see details below).…”

Gradual increase in thrombogenicity of juvenile platelets formed upon offset of prasugrel medication

“…[4][5][6][7][8][9] The thienopyridines clopidogrel and prasugrel are both prodrugs, which require metabolic conversion to form an active metabolite that irreversibly interacts with the P2Y 12 receptors of circulating platelets. 10 In contrast, ticagrelor is a reversible, non-competitive P2Y 12 antagonist (belonging to the cyto-pentyl-triazolo class of pyrimidines) interacting with the platelet receptors without metabolic conversion. [10][11][12] Due to the irreversible inhibition of the platelet P2Y 12 receptors by the active metabolites of clopidogrel and prasugrel, the formation of new platelets is required to recover platelet function.…”

“…10 In contrast, ticagrelor is a reversible, non-competitive P2Y 12 antagonist (belonging to the cyto-pentyl-triazolo class of pyrimidines) interacting with the platelet receptors without metabolic conversion. [10][11][12] Due to the irreversible inhibition of the platelet P2Y 12 receptors by the active metabolites of clopidogrel and prasugrel, the formation of new platelets is required to recover platelet function. 7,9 After ticagrelor treatment, recovery of platelet function is only determined by the elimination time of the drug (half-life of 8 h).…”

“…7,9 After ticagrelor treatment, recovery of platelet function is only determined by the elimination time of the drug (half-life of 8 h). 10 There is limited evidence that during the offset period of irreversible P2Y 12 inhibitors (usually prescribed for one year) patients may have an increased risk of a recurrent myocardial event. [13][14][15][16][17] This may point to hyperactivity of the newly formed platelets in the offset period, although the mechanism is unclear.…”