Abstract
Vicagrel, a novel acetate derivative of clopidogrel, exhibits a favorable safety profile and excellent antiplatelet activity. Studies aim at identifying genetic and non-genetic factors affecting vicagrel metabolic enzymes Cytochrome P450 2C19 (CYP2C19), Carboxylesterase (CES) 1 and 2 (CES1 and CES2), which may potentially lead to altered pharmacokinetics and pharmacodynamics, are warranted. A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating vicagrel and its metabolites was constructed, verified and validated in our study, which could simultaneously characterize its sequential two step metabolism and clinical response. Simulations were then performed to evaluate the effects of CYP2C19, CES1 and CES2 genetic polymorphisms as well as inhibitors of these enzymes on vicagrel pharmacokinetics and antiplatelet effects. Results suggested vicagrel was less influenced by CYP2C19 metabolic phenotypes and CES1 428 G > A variation, in comparison to clopidogrel. No pharmacokinetic difference in the active metabolite was also noted for volunteers carrying different CES2 genotypes. Omeprazole, a CYP2C19 inhibitor, and simvastatin, a CES1 and CES2 inhibitor, showed weak impact on the pharmacokinetics and pharmacodynamics of vicagrel. This is the first study proposing a dynamic PBPK/PD model of vicagrel able to capture its pharmacokinetic and pharmacodynamic profiles simultaneously. Simulations indicated that genetic polymorphisms and drug-drug interactions showed no clinical relevance for vicagrel, suggesting its potential advantages over clopidogrel for treatment of cardiovascular diseases. Our model can be utilized to support further clinical trial design aiming at exploring the effects of genetic polymorphisms and drug-drug interactions on PK and PD of this novel antiplatelet agent.
Highlights
Platelet P2Y12 receptor plays a crucial role in platelet activation
Physiologically based pharmacokinetic models (PBPK) models for clopidogrel and its two metabolites were constructed based on the work of Djebli N et al (Djebli et al, 2015) and optimized using our previous data obtained from healthy Chinese volunteers (Trial 1)
Comparable in vivo exposure of active thiol metabolite H4 (AM-H4) and inhibition on platelet aggregation (IPA) between vicagrel and clopidogrel were observed in extensive metabolizers (EM) subjects, especially during maintenance dose (MD) phase
Summary
Vessel damage stimulates the release of adenosine diphosphate (ADP) that binds to the P2Y12 receptor, which in turn leads to platelet activation and aggregation (Dorsam and Kunapuli, 2004; Cattaneo, 2015). P2Y12 receptor antagonists, e.g., thienopyridines bind to the P2Y12 receptor to block ADPmediated platelet activation and aggregation. Clopidogrel, a thienopyridine derivative, which targets P2Y12 receptor irreversibly, is widely used either alone or in combination with aspirin, remains a cornerstone of modern antiplatelet strategies (Hulot and Fuster, 2009). While the majority is hydrolyzed by carboxylesterase 1 (CES1) to an inactive carboxylic acid derivative, which accounts for 85% of the clopidogrel-related compounds circulating in plasma (Sangkuhl et al, 2010). 2-oxo-clopidogrel and AM-H4 are hydrolyzed by CES1 forming their respective inactive metabolites (Zhu et al, 2013)
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