Impacts of CYP2C19 genetic polymorphisms on bioavailability and effect on platelet adhesion of vicagrel, a novel thienopyridine P2Y₁₂ inhibitor

Abstract

Aims We investigated the impacts of CYP2C19 polymorphisms on pharmacokinetics and pharmacodynamics of vicagrel in healthy Chinese subjects. Methods CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs; 16 subjects/group) participated in a randomized, open‐label, 2‐period cross‐over study. Each study period lasted 7 days, with a loading dose of 24 mg of vicagrel or 300 mg of clopidogrel on day 1, and maintenance doses of 6 mg of vicagrel or 75 mg of clopidogrel daily from day 2 to day 7. The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 7. Results After a loading dose, the AUC0‐t of the active metabolite H4 by vicagrel was slightly lower in IMs and PMs (decreased by 21 and 27%, respectively) compared to EMs. Similar results were found after maintenance doses. In EMs, the AUC0‐t of H4 by vicagrel was somewhat higher than clopidogrel after the loading dose, and comparable with clopidogrel (90% confidence interval 0.94, 1.21) after the maintenance doses. However, it was much higher than clopidogrel in PMs, with a 1.28‐fold (loading dose) and a 73% (maintenance doses) increases compared to clopidogrel (P < 0.001). Consequently, the inhibition of platelet aggregation by vicagrel was greater than clopidogrel after both loading dose (28.2 vs 12.4% at 4 hours, P < 0.01) and maintenance doses (42.8 vs 24.6% at 4 hours, P < 0.001) in PMs. Conclusions CYP2C19 polymorphisms have less impact on vicagrel as compared to clopidogrel. Drug exposure and response to vicagrel in PMs were even higher than to clopidogrel in IMs.

Predicting the Effects of CYP2C19 and Carboxylesterases on Vicagrel, a Novel P2Y12 Antagonist, by Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Approach

“…Since CYP2C19 still participated in the second step of vicagrel metabolism (Qiu et al, 2014;Jiang et al, 2017), AM-H4 exposure and IPA slightly declined in PM volunteers comparing with those in EM and IM volunteers ( Supplementary Table 3 and Figure 4), which might not be clinically relevant. The results confirmed the assumption in previous studies that dosage adjustment or alternative therapy was unnecessary for patients identified as CYP2C19 PM phenotype receiving vicagrel treatment (Zhang et al, 2020).…”

“…2-oxo-clopidogrel is further metabolized by CYPs, i.e. CYP3A4, CYP2B6, CYP2C9 and CYP2C19 to form AM-H4, which is the same for both clopidogrel and vicagrel (Kazui et al, 2010;Zhang et al, 2020) ( Supplementary Figure 1). Due to the much faster and more efficient formation of 2-oxo-clopidogrel in the gut than clopidogrel in the liver, it is anticipated to produce AM-H4 more efficiently and consistently than clopidogrel (Shan et al, 2012).…”

Physiologically-Based Pharmacokinetic-Pharmacodynamics Model Characterizing CYP2C19 Polymorphisms to Predict Clopidogrel Pharmacokinetics and Its Anti-Platelet Aggregation Effect Following Oral Administration to Coronary Artery Disease Patients With or Without Diabetes

“…The first order conditional estimation of the Lindstrom-Bates method was used in the simulation. For pharmacokinetic validation, the variances of V max,CYP2C19 , CL int,CES1 and K t,i with standard deviation of intra-individual error were estimated using four sets of observed CLOP-AM plasma concentration-time profiles in healthy subjects ( Kobayashi et al, 2015 ; Umemura and Iwaki, 2016 ; Song et al, 2018 ; Zhang et al, 2020 ). For pharmacodynamic validation, the variances of V max,CYP2C19 , CL int,CES1 , K t,i , and k irre were also estimated with three sets of reported IPA-time profiles in healthy individuals ( Kim et al, 2008 ; Kobayashi et al, 2015 ; Kim et al, 2016 ).…”

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“…A total of six available clinical studies of vicagrel and clopidogrel which determined AM-H4 plasma concentrations and/or IPA were included in this study [Trial 1 (Liu et al, 2015), Trial 2 (Angiolillo et al, 2011), Trial 3 (Simon et al, 2011), Trial 4 (Li et al, 2018), Trial 5 (Zhang et al, 2020) and Trial 6 (Tarkiainen et al, 2015)]. Detailed clinical trial information was described in Supplementary Table 1.…”

“…Vicagrel is now in Phase III development in China, suggesting the potential as a novel antiplatelet drug for cardiovascular diseases. Several clinical studies have demonstrated a favorable safety profile and excellent antiplatelet activity of vicagrel (Li et al, 2018;Liu et al, 2019;Zhang et al, 2020). Considering the involvement of carboxylesterases and CYP2C19 in vicagrel metabolism and the contribution of genetic variants and inhibitors of CYP2C19 and CES1 to the interindividual variability in clopidogrel pharmacokinetics and pharmacodynamics, further studies are still warranted to clarify such effects on vicagrel.…”