Pharmacokinetic and Pharmacodynamic Responses to Clopidogrel: Evidences and Perspectives

Zhang, Yan-Jiao; Li, Mu-Peng; Tang, Jie; Chen, Xiaoping

doi:10.3390/ijerph14030301

Cited by 41 publications

(34 citation statements)

References 117 publications

(132 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous studies have demonstrated that suboptimal response to antiplatelet agents was affected by many factors 18, 19. Simple linear regression analysis showed that the inhibitory rate of ADP pathway may be associated with age, sex, OSA, hypertension, eGFR, platelet counts and β‐blockers ( P <0.1) (Table S1).…”

Section: Resultsmentioning

confidence: 90%

Impact of Obstructive Sleep Apnea on Platelet Function Profiles in Patients With Acute Coronary Syndrome Taking Dual Antiplatelet Therapy

Gong

Xiao

Fan

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundObstructive sleep apnea (OSA) is a novel risk factor for acute coronary syndrome (ACS). Several studies have shown OSA to be associated with induced platelet reactivity. However, whether OSA have effects on platelet function profiles in ACS patients taking dual antiplatelet therapy remains unexplored.Methods and ResultsThis was a cross‐sectional observational study, in which ACS patients taking maintenance aspirin and clopidogrel therapy were included. OSA was defined as an apnea‐hypopnea index ≥15 events/hour. The inhibitory rate of arachidonic acid or adenosine diphosphate pathway were assessed with thrombelastography and defined patients with high residual on‐treatment platelet reactivity. Platelet indices were obtained from routine analysis of blood samples using an automated blood cell counter. A total of 127 ACS patients taking dual antiplatelet therapy were analyzed. Platelet volume indices, including mean platelet volume and platelet large cell ratio, were significantly increased in patients with OSA. Patients with OSA (n=68) had significantly lower inhibitory rate of adenosine diphosphate receptor pathway (P=0.028) compared with those without (n=59). After adjustment for potential confounders, patients with OSA were more likely to have high residual on‐treatment platelet reactivity after clopidogrel therapy (adjusted odds ratio: 3.25, 95% confidence interval: 1.19–8.87, P=0.021).ConclusionsIn ACS patients taking dual antiplatelet therapy, OSA is associated with an increased level of platelet volume indices, reduced clopidogrel‐induced antiplatelet effects and a greater prevalence of high residual on‐treatment platelet reactivity.

show abstract

Section: Resultsmentioning

confidence: 90%

Impact of Obstructive Sleep Apnea on Platelet Function Profiles in Patients With Acute Coronary Syndrome Taking Dual Antiplatelet Therapy

Gong

Xiao

Fan

et al. 2018

JAHA

View full text Add to dashboard Cite

show abstract

“…Because of the highly variable PK and PD results for vicagrel in all treatment groups, the carboxyl esterase-related polymorphisms should be investigated in future studies. And except for the occurrence of SNPs, the variable response to antiplatelet agents may relate to different non-genetic factors when administered to patients, such as demographic characteristics (age, BMI, smoking…), concurrent diseases, and drug interactions (Zhang et al, 2017 ). These factors will be considered in further studies among patients.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Tolerability, Pharmacokinetics and Pharmacodynamics of Vicagrel, a Novel P2Y12 Antagonist, in Healthy Chinese Volunteers

Liu

Zhu

et al. 2018

Front. Pharmacol.

View full text Add to dashboard Cite

Background: Vicagrel is a novel anti-platelet drug and hydrolyzed to the same intermediate as clopidogrel via esterase, instead of CYP2C19. Here we report the first clinical trial on the tolerability, pharmacokinetics and pharmacodynamics of different doses of vicagrel, and comparison with clopidogrel in healthy Chinese volunteers.Methods: This study was conducted in two parts. Study I was a dose-escalating (5–15 mg) study. For each dose, 15 participants were randomized into three groups (total n = 45); nine participants were given vicagrel, three were given clopidogrel, and three were given a placebo. Study II was conducted to assess interactions between vicagrel and aspirin in 15 healthy participants. The plasma concentrations of the metabolites of vicagrel and clopidogrel were determined using a LC-MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y12 assay.Results: Vicagrel (5–15 mg per day) dosing for 10 days or addition of aspirin was well tolerated in healthy volunteers. The exposure of the active metabolite increased proportionally across the dose range and was higher (~10-fold) than clopidogrel. The levels of IPA dosing 75 mg clopidogrel were between the responses of 5 mg and 10 mg vicagrel. After a single loading dose of vicagrel (30 mg) and a once-daily maintenance dose (7.5 mg) for 8 days, the maximum inhibition of platelet aggregation was similar to that seen with the combined use of vicagrel and aspirin (100 mg/day).Conclusion: Oral vicagrel demonstrated a favorable safety profile and excellent anti-platelet activity, which could be a promising P2Y12 antagonist as anti-platelet drug and can be further developed in phase II/III studies, and marketing for the unmet medical needs of cardiovascular diseases. The study was registered at http://www.chictr.org.cn (ChiCTR-IIR-16009260).

show abstract

“…Clopidogrel is a prodrug and is transformed into the active metabolite H4 by several cytochrome P450 (CYP450) isoenzymes. A substantial number of clinical trials have observed that CYP450 genetic polymorphisms, especially the CYP2C19 loss-of-function ( CYP2C19 * 2 and CYP2C19 * 3 ) and/or gain-of-function ( CYP2C19 * 17 ) variants, can affect the antiplatelet efficacy of clopidogrel and the clinical outcomes (Chen et al, 2008a ; Paré et al, 2010 ; Zhang et al, 2015b , 2017 ; Sun et al, 2016 ). Evidences showed that the CYP2C19 intermediate metabolizers (IM, genotyped as CYP2C19 * 1 * 2 or CYP2C19 * 1/ * 3 ) and CYP2C19 poor metabolizers (PM, genotyped as CYP2C19 * 2/ * 2, CYP2C19 * 2/ * 3 , or CYP2C19 * 3 * 3 ) showed obviously increased risk of recurrence of ischemic events than CYP2C19 extensive metabolizers (EM, genotyped as CYP2C19 * 1 * 1 ) after PCI (Mega et al, 2010 ; Mao et al, 2013 ; Zhong et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Association of N6AMT1 rs2254638 Polymorphism With Clopidogrel Response in Chinese Patients With Coronary Artery Disease

Zhang

et al. 2018

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Dual antiplatelet treatment with aspirin and clopidogrel is the standard therapy for patients undergoing percutaneous coronary intervention (PCI). However, a portion of patients suffer from clopidogrel resistance (CR) and consequently with recurrence of cardiovascular events. Genetic factors such as loss-of-function variants of CYP2C19 contribute a lot to CR. Recently, the N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) rs2254638 polymorphism is reported to be associated with clopidogrel response. To validate the association between N6AMT1 rs2254638 polymorphism and clopidogrel response, 435 Chinese CAD patients receiving aspirin and clopidogrel were recruited. N6AMT1 rs2254638 and CYP2C19*2/*3 polymorphisms were genotyped. Platelet reaction index (PRI) was measured by VASP-phosphorylation assay after treated with a 300 mg loading dose (LD) clopidogrel or 75 mg daily maintenance dose (MD) clopidogrel for at least 5 days. There was a significant difference in PRI between LD cohort and MD cohort. Carriers of CYP2C19*2 allele showed significantly increased PRI in the entire cohort and in respective of the MD and LD cohorts (p < 0.001, p = 0.003, p < 0.001, respectively). However, carriers of CYP2C19*3 allele exhibited significantly higher PRI only in the entire cohort and LD cohort (p = 0.023, p = 0.023 respectively). PRI value was significantly higher in CYP2C19 PM genotyped patients as compared with those carrying the IM genotypes and EM genotype (p < 0.001). Besides, carriers of the rs2254638 C allele showed significantly higher PRI in entire cohort and in the LD cohort (p = 0.023, p = 0.008, respectively). When the patients were grouped into clopidogrel resistance (CR) and non-clopidogrel resistance (non-CR) groups, CYP2C19*2 was associated with increased risk of CR in the entire cohort, the LD cohort and the MD cohort (p < 0.001, p < 0.001, and p = 0.019, respectively). Carriers of the rs2254638 C allele also showed increased risk of CR in the entire cohort and the LD cohort (p = 0.024, and p = 0.028, respectively). N6AMT1 rs2254638 remained as a strong predictor for CR (TC vs. TT: OR = 1.880, 95% CI = 1.099–3.216,p = 0.021; CC vs. TT: OR = 1.930, 95% CI = 1.056-3.527, p = 0.032; TC + CC vs. TT: OR = 1.846, 95%CI = 1.126–3.026, p = 0.015) after adjustment for confounding factors. Our study confirmed the influence of CYP2C19*2 and rs2254638 polymorphisms on clopidogrel resistance in Chinese CAD patients. Both CYP2C19*2 and N6AMT1 rs2254638 polymorphism may serve as independent biomarkers to predict CR.

show abstract

Pharmacokinetic and Pharmacodynamic Responses to Clopidogrel: Evidences and Perspectives

Cited by 41 publications

References 117 publications

Impact of Obstructive Sleep Apnea on Platelet Function Profiles in Patients With Acute Coronary Syndrome Taking Dual Antiplatelet Therapy

Impact of Obstructive Sleep Apnea on Platelet Function Profiles in Patients With Acute Coronary Syndrome Taking Dual Antiplatelet Therapy

Evaluation of Tolerability, Pharmacokinetics and Pharmacodynamics of Vicagrel, a Novel P2Y12 Antagonist, in Healthy Chinese Volunteers

Association of N6AMT1 rs2254638 Polymorphism With Clopidogrel Response in Chinese Patients With Coronary Artery Disease

Contact Info

Product

Resources

About