Investigation of bidirectional pharmacokinetic drug-drug interaction between vicagrel, a novel analogue for the antiplatelet drug clopidogrel, and atorvastatin

Research Aim 1)To investigate the risk and mechanisms of a possible bidirectional pharmacokinetic drug-drug interaction (DDI) between vicagrel, a potential replacement drug for the antiplatelet drug clopidogrel, and atorvastatin, a cardiovascular drug often used in clinical combination; 2)To develop a novel complex physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model that can describe concentration-time profiles of atorvastatin, vicagrel and its active metabolite(AM) as well as its pharmacodynamic effect (anti-platelet activity), and can predict DDIs between those two drugs that may be both perpetrators and victims; 3)To provide information on the potential interactions for clinical use, including whether the drug dose or dosing interval should be adjusted in the event of a DDI. Background The risk of drug-drug interaction between clopidogrel and atorvastatin, two cardiovascular drugs often used in clinical combination, has been proved to be insignificant in combination use in clinical. However, the risks have not yet been fully evaluated when atorvastatin is combined with a series of clopidogrel analogs which have been developed to overcome clopidogrel resistance in the Chinese population. Apparently different from the clopidogrel bioactivation pathway, vicagrel undergoes complete first-pass metabolism in the intestine to produce high concentrations of 2-oxo-clopidogrel via carboxylesterase-2 (CES2) and arylacetamide deacetylase (AADAC) and the subsequent active metabolite by CYP450s in the intestine and liver. Thus, although 2-oxo-clopidogrel is not considered a possible perpetrator in the clopidogrel-related DDIs due to its very low systemic concentration, the highly elevated 2-oxo-clopidogrel concentration following administration of vicagrel may have an effect on atorvastatin via inhibition of CYP3A4 and OATP1B1. In addition, atorvastatin has also been reported to show a significant inhibitory effect on the vicagrel hydrolysis via CES2 and AADAC. Hypothesis Firstly, atorvastatin may reduce the bioactivation of vicagrel by inhibition of intestinal CES2 and AADAC as well as intestinal and hepatic CYP3A4, thereby attenuating the anti-platelet activity of vicagrel. Secondly, high concentrations of 2-oxo-clopidogrel after vicagrel administration, which may be lower than vicagrel taken alone but should still be much higher than that in the case of clopidogrel, may inhibit atorvastatin metabolism via intestinal and hepatic CYP3A4 and hepatic OATP1B1 and increase the risk of adverse reactions of atorvastatin.