Clinical pharmacokinetics and pharmacodynamics of clopidogrel

Abstract

Acute coronary syndromes (ACS) remain life-threatening disorders, which are associated with high morbidity and mortality. Dual antiplatelet therapy with aspirin and clopidogrel has been shown to reduce cardiovascular events in patients with ACS. However, there is substantial inter-individual variability in the response to clopidogrel treatment, in addition to prolonged recovery of platelet reactivity as a result of irreversible binding to P2Y12 receptors. This high inter-individual variability in treatment response has primarily been associated with genetic polymorphisms in the genes encoding for cytochrome (CYP) 2C19, which affect the pharmacokinetics of clopidogrel. While the US Food and Drug Administration has issued a boxed warning for CYP2C19 poor metabolizers because of potentially reduced efficacy in these patients, results from multivariate analyses suggest that additional factors, including age, sex, obesity, concurrent diseases and drug-drug interactions, may all contribute to the overall between-subject variability in treatment response. However, the extent to which each of these factors contributes to the overall variability, and how they are interrelated, is currently unclear. The objective of this review article is to provide a comprehensive update on the different factors that influence the pharmacokinetics and pharmacodynamics of clopidogrel and how they mechanistically contribute to inter-individual differences in the response to clopidogrel treatment.

Figure 1

Clopidogrel is an orally administered pro-drug. In the liver, approximately 15% of absorbed clopidogrel is metabolized by the cytochrome P450 (CYP) system to generate its active metabolite via a 2-step bioactivation process, whereas the rest 85% is hydrolyzed by carboxylesterase 1 (CES1) to an inactive carboxylic acid derivative. CES1 also catalyzes the hydrolysis of the intermediate metabolite 2-oxo-clopidogrel and the active metabolite. The active metabolite binds to the adenosine diphosphate (ADP) P2Y₁₂ receptor on the surface of platelet and leads to an irreversible inhibition of platelet aggregation. ADP binds to the G_q-coupled P2Y₁ receptor, which activates phospholipase C (PLC) that forms inositol triphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol bisphosphate (PIP2). IP3 causes mobilization of intracellular calcium, whereas DAG activates protein kinase C (PKC) and leads to phosphorylation of myosin light chain kinase (MLCK-P). These two processes both lead to initiation of platelet aggregation. On the other hand, activation of P2Y₁ receptor coupled G₁₂, another G-protein, which activates the “Rho” protein, as well as activation of P2X₁ receptor by adenosine triphosphate (ATP), which causes extracellular calcium influx, both lead to change of platelet shape. Activation of the Gi-coupled P2Y₁₂ receptor by ADP leads to release of the α_i and β_γ subunits, which ultimately lead to stabilization of platelet aggregation. The α_i subunit inhibits adenylyl cyclase (AC), which decreases intracellular levels of cyclic adenosine monophosphate (cAMP), reduces cAMP-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) (VASP-P), and modulates activation of glycoprotein (GP) IIb/IIIa receptor. The β_γ subunit activates the phosphatidylinositol 3-kinase (PI3K), which in turn, cause activation of a serine-threonine protein kinase B (PKB/Akt) and of Rap1b GTP binding proteins and causes activation of GP IIb/IIIa receptor. In addition, Prostaglandin E₁ (PGE₁) elevates cAMP and VASP-P levels via activation of AC. Solid arrows represent activation, dashed arrows represent inhibition (This figure is modified from Angiolillo, DJ et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. Am Coll Cardiol. 2007 Apr 10;49(14):1505–16 [3]).

Figure 2

Prevalence of patients with high on-treatment platelet reactivity (HPR) according to age, body mass index and diabetes mellitus status. HPR was defined as residual platelet aggregation (RPA) > 14%, which was assessed by light transmittance aggregometry (LTA) assay with ADP 5 μmol/L following a 600 mg of clopidogrel loading dose in 760 patients undergoing elective coronary stent implantation [41].