Pharmacodynamics Of Clopidogrel Research Articles

Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis Patients

IntroductionPatients undergoing hemodialysis (HDP) exhibit extensive cardiovascular risk. The widely prescribed anti-platelet agent clopidogrel is metabolically activated by cytochrome enzymes, which may be impaired by uremia and chronic low-grade inflammation, typically present in HDP. We conducted a prospective multicenter study to investigate the pharmacokinetics and pharmacodynamics of clopidogrel in HDP and healthy volunteers (HV). MethodsWe enrolled HDP receiving long-term clopidogrel (75mg) and pantoprazole treatment (40 mg). HV received a loading dose of 300 mg clopidogrel, followed by 75 mg once daily. Pantoprazole, a substrate and probe drug of CYP2C19, was administered intravenously (40 mg). Plasma concentrations were quantified by mass spectrometry. Pharmacokinetics were calculated, and a population pharmacokinetic model was developed. The primary endpoint was the maximum concentration of clopidogrel’s active metabolite (Cmax_CAM). Platelet aggregation was measured using ADP-induced whole-blood aggregometry. ResultsSeventeen HDP and 16 HV were included. Cmax_CAM was significantly lower in HDP compared to HV (median [IQR] 12.2 [4.6-23.4] vs. 24.7 [17.8-36.5] ng/mL, p=0.02). The Cmax ratio of CAM to prodrug was 8.5-fold lower in HDP, and an 82.7% reduced clopidogrel clearance, including CAM formation, was found using population pharmacokinetic modeling. ADP-induced platelet aggregation at 120 min was significantly higher in HDP than in HV (median [IQR]: 26 [14-43] vs. 12 [11-18] U, p=0.004. Pantoprazole terminal half-life was ∼1.7-fold higher in HDPs compared to HVs. ConclusionOur data demonstrate an altered metabolism of clopidogrel in HDP in the context of lower CYP2C19 activity, with potential implications for other substances metabolized by this enzyme.

Effects of ilaprazole on the steady-state pharmacodynamics of clopidogrel in healthy volunteers: An open-label randomized crossover study.

Background: Previous studies have suggested that proton pump inhibitors could impair the antiplatelet effect of clopidogrel. It is uncertain whether ilaprazole affects the antiplatelet effect of clopidogrel. This study aimed to determine the drug-drug interaction between ilaprazole and clopidogrel. Methods: A randomized crossover trial of 40 healthy subjects was performed. Clopidogrel was administered alone or in combination with ilaprazole for 7 days. The maximal platelet aggregation (MPA) to 5 μmol/L adenosine diphosphate was measured by light transmission aggregometry and the platelet reactivity index (PRI) was determined by vasodilator-stimulated phosphoprotein P2Y12 assay. High on-treatment platelet reactivity (HOPR) was defined as a MPA of >40%. The inhibition of platelet aggregation (IPA) and PRI in the two phases were compared between two regimens after the last dosing. Results: IPA was comparable between the two regimens at 0, 10 and 24 h (p > 0.05), but higher at 4 h in the clopidogrel alone regimen compared with that in the combined treatment regimen (75.66 ± 18.44% vs. 70.18 ± 17.67%, p = 0.031). The inhibition of PRI was comparable between the two regimens at 0 and 24 h. There were no significant differences in the area under the time-IPA% curve (AUC) or the incidence of HOPR at all time-points between the two regimens. Conclusion: In healthy subjects, ilaprazole has limited effect on the pharmacodynamics of clopidogrel and it may not be clinically relevant. Clinical Trial Registration: [www.chictr.org.cn], identifier [ChiCTR2000031482].

Interaction study of salvianolic acids for injection on pharmacokinetics of clopidogrel in rats using LC-MS/MS.

Salvianolic acids for injection (SAI) is developed from traditional Chinese medicine and approved for the treatment of cardiovascular and cerebrovascular diseases. Clopidogrel is an inhibitor of platelet aggregation, which is often prescribed for patients in combination with SAI. This present study aimed to assess the effects of SAI on the pharmacogenomics, pharmacokinetics, and pharmacodynamics of clopidogrel, thereby ensuring the safety and efficacy of coadministration. In vitro cytochrome P450 isoenzyme assays were performed in human liver microsomes using LC-MS/MS method to assess the metabolites of CYPs substrates. The effects of SAI on the pharmacokinetic and pharmacodynamic behaviors of clopidogrel were investigated in rats. The main pharmacokinetic parameters were analyzed using LC-MS/MS. Prothrombin time, activated partial thromboplastin time, bleeding time, and inhibition of platelet aggregation were measured to evaluate the effects of pharmacodynamics. Our study revealed that the clinical dose of SAI has no significant inhibitory effect on clopidogrel-related liver microsome metabolic CYP450 isoenzymes. Moreover, SAI did not affect the pharmacokinetics of clopidogrel when rats were administered both single and multiple doses. In pharmacodynamic study, SAI has no effect on platelet aggregation rate, prothrombin time, and activated partial thromboplastin time of clopidogrel but could significantly prevent the risk of bleeding caused by clopidogrel.

Dosage optimization of clopidogrel via a precision medicine approach: the way forward.

Clopidogrel is a prodrug chiefly metabolized by the hepatic isoenzyme CYP2C19 to its active metabolite that inhibits the platelet aggregation. It has been proven in many populations that the genetic polymorphism of CYP2C19 has influence on the pharmacokinetic and or pharmacodynamics of this drug and resulting in high inter-individual variability in the treatment outcomes. As CYP2C19 genetic polymorphism is highly prevalent among the Asian population, the influence of the same on the pharmacokinetics and; thereby, the pharmacodynamics of clopidogrel needs more attention. Using the pharmacogenetic information for drug therapy could help overcome these issues and to optimize the dosage regimen of clopidogrel, this review advocates the precision medicine approach for reducing the clopidogrel resistance and adverse cardiovascular events.

Clopidogrel-herb Interactions: A Pharmacokinetic and Pharmacodynamic Assessment in a Rat Model.

Herbs usually contain a mixture of biologically active constituents, which can interact with numerous prescribed drugs and alter their safety profiles. The current investigation was aimed to evaluate the effect of commonly used herbal products including black seed (Nigella sativa), garden cress (Lepidium sativum), and fenugreek (Trigonella foenum-graecum) on the pharmacokinetics and pharmacodynamics of clopidogrel using a Wistar rat model. A GC-MS analysis revealed the presence of several phytoconstitutents (polyphenols) in the extracts of black seed, garden cress, and fenugreek. These polyphenols have the potential to interfere with clopidogrel effect. Plasma concentrations of clopidogrel were measured at different time points in the absence and presence of the concurrent use of tested herbal products and the pharmacokinetic parameters were calculated. Bleeding time was measured in various groups as a measure of the antiplatelet effect of clopidogrel. Area under the plasma concentration-time curves (AUC0-∞) of clopidogrel were 35.53 ±0.89 μg/ml*h (p<0.05), 26.01 ±0.90 μg/ml*h (p>0.05) and 32.80 ±2.51 μg/ml*h (p<0.05) in the black seed, garden cress and fenugreek group, respectively, compared with that of the control group (27.02 ±0.42 μg/ml*h). Treatment with black seed also caused an increase in clopidogrel Cmax by 31.52% (p<0.05) and with fenugreek by 21.42% (p<0.05); Cmax, did not changed with garden cress treatment (6.48 ±0.15 μg/ml versus 6.12 ±0.21 μg/ml, p>0.05). The pharmacodynamic evaluation of the antiplatelet effect of clopidogrel in the presence of herbal products treatment showed a significant prolongation in the bleeding time from a control baseline by ~22-26%, and by added ~8-12% in reference to clopidogrel therapeutic effect (p<0.05). The concurrent use of black seed, fenugreek, or garden cress can alter the pharmacokinetics and pharmacodynamics of clopidogrel to varying degrees due to the presence of various bioactive polyphenols. This is probably due to changes in drug disposition and its antiplatelet action. Further confirmation can determine the clinical relevance of these observations and identify the exact constituents responsible for such activities.

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss‐of‐function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate‐induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e−33). After correction for CYP2C19*2 no other single‐nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e−09, 4.53e−08, and 2.60e−10, respectively). CYP2C19*2 is the strongest genetic determinant of on‐clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.

Effect of Smoking Cessation on the Pharmacokinetics and Pharmacodynamics of Clopidogrel after PCI: The Smoking Cessation Paradox Study.

Cigarette smoking is associated with enhanced clopidogrel effect and platelet inhibition. However, the effect of smoking cessation on clopidogrel pharmacokinetics (PK) and pharmacodynamics (PD) is unknown. We aimed to determine the effect of smoking cessation, confirmed by cotinine measurement, on clopidogrel PK and PD after percutaneous coronary intervention (PCI). Following successful PCI, patients treated with 75 mg/day clopidogrel who reported smoking ≥10 cigarettes/day with NicAlert urine cotinine level 6 were enrolled. Clopidogrel and its metabolite concentrations, VerifyNow P2Y12 reaction units (PRUs), and NicAlert levels were measured in the study group before and at 30 days after smoking cessation and in a control group. CYP1A2 and CYP2C19 genotypes were determined. At 30-day visit (n = 87), 45 patients continued smoking, whereas 42 patients stopped smoking. Baseline PRUs were similar between groups. At 30 days, the smoking cessation group had higher PRUs (150.5 ± 68.6 vs. 118.4 ± 65.9, p = 0.03), greater absolute PRU change (27.7 ± 39.8 vs. -12.9 ± 55.4, p = 0.0002), greater change of PRUs adjusted for baseline platelet reactivity (38.6 ± 10.0, p < 0.01), greater risk of high platelet reactivity (HPR) (odds ratio: 10.14 [1.52-67.5], p = 0.017), and a trend towards decreased H3 clopidogrel metabolite levels (-3.41 ng/mL [-11.00 to 0.54 ng/mL], p = 0.072). CYP2C19 LoF carriers who stopped smoking had the highest PRUs, whereas those with the wild type who continued smoking had the lowest PRUs (p < 0.008). Smoking cessation in clopidogrel-treated patients after PCI is associated with increased platelet reactivity and greater risk of HPR. Alternative P2Y12 inhibitors may be considered in selected patients who stop smoking after PCI.

Impact of genetic variants of selected cytochrome P450 isoenzymes on pharmacokinetics and pharmacodynamics of clopidogrel in patients co-treated with atorvastatin or rosuvastatin.

Impaired antiplatelet effect of clopidogrel (CLP) can result from drug-drug interactions and genetic polymorphisms of drug-metabolizing enzymes. The aim of the study was to evaluate the effect of genetic polymorphisms of ABCB1 and the selected cytochrome P450 isoenzymes on the pharmacodynamics and pharmacokinetics of CLP and its metabolites in patients co-treated with atorvastatin or rosuvastatin. The study involved 50 patients after coronary angiography/angioplasty treated with CLP and atorvastatin (n= 25) or rosuvastatin (n= 25) for at least 6months. Plasma concentrations of CLP, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive CLP carboxylic acid metabolite were measured by UPLC-MS/MS method. Identification of the CYP2C19*2, CYP2C19*17, CYP3A4*1G, CYP1A2*1F, and ABCB1 C3435T genetic polymorphisms was performed by PCR-RFLP, while platelet reactivity units (PRU) were tested using the VerifyNow P2Y12 assay. There were significant differences in the pharmacokinetic parameters of the H4 active metabolite of CLP in the atorvastatin and rosuvastatin group divided according to their CYP2C19 genotype. There were no significant associations between CYP3A4, CYP1A2, and ABCB1 genotypes and pharmacokinetic parameters in either statin groups. In the multivariate analysis, CYP2C19*2 genotype and non-genetic factors including BMI, age, and diabetes significantly affected platelet reactivity in the studied groups of patients (P< 0.01). In the atorvastatin group, CYP2C19*2, CYP3A4*1G, and ABCB1 C3435T TT genotypes were independent determinants of PRU values (P< 0.01). The CYP2C19*2 allele is the primary determinant of the exposition to the H4 active metabolite of clopidogrel and platelet reactivity in patients co-treated with atorvastatin or rosuvastatin.

ASSOCIATION BETWEEN SMOKING AND THE ANTIPLATELET EFFECT OF CLOPIDOGREL

Clopidogrel is the most widely used P2Y12 inhibitor, which is administered for secondary prevention of atherothrombotic events in patients with cardiovascular disease after myocardial infarction and coronary stenting. Given the complexity of the clopidogrel metabolism and variety of potential drug-drug interactions, the issue of individual variability of its antiplatelet effects is of paramount concern. Another issue of clinical relevance is related to so-called “smoker’s paradox”. This phenomenon implies that in some patients smoking is associated with increased antiplatelet potency of clopidogrel. In this review, we analyze recent international data on the features of pharmacokinetics and pharmacodynamics of clopidogrel, plausible mechanisms of the “smoker’s paradox” and its clinical significance in patients with coronary artery disease. Comparative efficacy of available P2Y12 inhibitors and possible implications of smoking are considered. Pharmacogenetic aspects and the issues of personalized antiplatelet therapy are discussed.

Influence of statin treatment on pharmacokinetics and pharmacodynamics of clopidogrel and its metabolites in patients after coronary angiography/angioplasty

Possible interaction between clopidogrel and CYP3A4-metabolised atorvastatin or non-CYP3A4-metabolised rosuvastatin was investigated based on pharmacokinetic parameters of clopidogrel and its metabolites as well as the platelet reactivity test in patients undergoing coronary angiography/angioplasty.The study involved 50 patients (62.7 ± 7.8 years old) who underwent coronary angiography/angioplasty and were treated with clopidogrel and atorvastatin or rosuvastatin during the six months after the procedure. The P2Y12 reaction units (PRU) and pharmacokinetic parameters of clopidogrel, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive carboxylic metabolite were measured 12–18 h and six months after the coronary angiography/angioplasty.There were no significant differences in concentrations of clopidogrel and its metabolites including the H4 active metabolite in plasma of patients co-treated with clopidogrel and atorvastatin or rosuvastatin. The use of statins did not affect the pharmacokinetic parameters of the studied compounds. A significant correlation was found between the Cmax and AUC0-t of the active H4 isomer and platelet aggregation in a group of patients treated with rosuvastatin but not in the atorvastatin group. No significant differences in PRU values were observed between the atorvastatin and rosuvastatin groups at the beginning of the study (171.4 ± 54.3 vs 146.3 ± 48.1 PRU, p = 0.192) as well as at six months (173.7 ± 45.8 vs 157.3 ± 54.9 PRU, p = 0.562). However, in a small group of patients, who were discharged from atorvastatin to rosuvastatin, an increase in the PRU values accompanied by a decreased AUC of the H4 active isomer was observed.The study confirmed that the systemic exposure to clopidogrel and its active H4 isomer of thiol metabolite, as well as the antiplatelet effect of the drug, were not negatively affected by co-administration of atorvastatin as compared with rosuvastatin.

Effects of Danshen capsules on the pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers

Nowadays, the Herb-drug combination is becoming increasingly popular in China. However, the possible interaction induced by their combination was examined rarely. The aim of this study was to investigate the effect of multi-dose administration of Danshen capsules on clopidogrel pharmacokinetics and pharmacodynamics in healthy volunteers. A sequential, open-label, and two-period pharmacokinetic drug interaction study was designed to compare clopidogrel pharmacokinetic parameters before and after 7 days of administration of Danshen capsules in twenty healthy male volunteers. Co-administration of multiple doses of Danshen capsules caused increases in apparent oral clearance of clopidogrel and its metabolite by 96.5% and 73.7% and apparent volume of distribution by 94.2% and 75.1%, corresponding declines in Cmax by 41.7% and 32.9%, AUC0-t by 50.3% and 41.8%, and AUC0-∞ by 49.3% and 41.5% in human volunteers, respectively. Corresponding pharmacokinetic findings, co-administration of Danshen capsules with clopidogrel decreased the antiplatelet activity compared with individual agents. The results suggested that multiple dose administration of Danshen capsules could induce cytochrome P450 (CYP) isoenzymes, thereby increasing the clearance of clopidogrel. Therefore, caution should be taken when Danshen products containing lipophilic components are used in combination with therapeutic drugs metabolized by CYP3A4.

Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points—Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC)

The P2Y12 receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response. Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and genome-wide studies. In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate-stimulated platelet function tests included vasodilator-stimulated phosphoprotein assay, light transmittance aggregometry, and the VerifyNow P2Y12 assay. A proof-of-principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (P value=5.1 × 10-40). The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.

Impact of (CYP3A Inhibiting) Antiretroviral Treatment on the Pharmacokinetics and Pharmacodynamics of Clopidogrel and Prasugrel

HIV patients are at high risk of developing a cardiovascular disease because of HIV-related vascular complications and adverse effects of their antiretroviral treatment. Clopidogrel and prasugrel are the main antiplatelet agents indicated to prevent ischemic events. These pro-drugs are bioactivated via various cytochromes including CYP3A, CYP2B6 and CYP2C19. Ritonavir and cobicistat, an analogue of ritonavir, are commonly used to increase the bioavailability of protease inhibitors and elvitegravir through inhibition of CYP3A. Consequently, they may inhibit prasugrel and clopidogrel bioactivation pathways and reduce their efficacy. The aim of this study was to assess the potential drug-drug interaction between clopidogrel, prasugrel and ritonavir/cobicistat. A randomized cross-over clinical study was conducted on healthy subjects and HIV patients under ritonavir-boosted or cobicistat-boosted antiretroviral treatments. The pharmacodynamic effect of single doses of clopidogrel 300mg and prasugrel 60mg was compared. To this end, the platelet reactivity index (PRI) was evaluated by vasodilator-stimulated phosphoprotein (VASP) assay. Additionally, the pharmacokinetic profiles of clopidogrel and prasugrel active metabolites were assessed. The formation of active metabolites was significantly lower in HIV patients compared to healthy subjects. In terms of pharmacodynamic effect, platelet inhibition was comparable in both groups.Tabled 1Healthy Volunteers (n=8)HIV Patients (n=12)p-value*Clopidogrel AMAUC (ng*h/mL)80.5 (62.6 – 114.9)26.0 (7.9 – 71.6)0.012**PRI %51.3% (45.4% – 69.6%)40.6% (34.0% – 71.4%)0.779Prasugrel AMAUC (ng*h/mL)396 (351– 462)203 (143 – 306)0.012**PRI%2.7% (2.0% – 6.3%)4.9% (2.9% – 12.4%)0.183Values are expressed as geometric means (IC95%)AM : Active metabolite; AUC : Area Under Concentration-time curve* Wilcoxon signed-rank test; ** Highly significant Open table in a new tab Values are expressed as geometric means (IC95%) AM : Active metabolite; AUC : Area Under Concentration-time curve * Wilcoxon signed-rank test; ** Highly significant Although ritonavir and cobicistat are associated with a lower exposure to clopidogrel and prasugrel active metabolites, no impact on the pharmacodynamics of these two antiplatelet agents was demonstrated.

Haplotype of platelet receptor P2RY12 gene is associated with residual clopidogrel on-treatment platelet reactivity.

To investigate a possible association between common variations of the P2RY12 and the residual clopidogrel on-treatment platelet reactivity after adjusting for the influence of CYP2C19 tested by thromboelastography (TEG). One hundred and eighty patients with acute coronary syndrome (ACS) treated with clopidogrel and aspirin were included and platelet function was assessed by TEG. Five selected P2RY12 single nucleotide polymorphisms (SNPs; rs6798347, rs6787801, rs6801273, rs6785930, and rs2046934), which cover the common variations in the P2RY12 gene and its regulatory regions, and three CYP2C19 SNPs (*2,*3,*17) were genotyped and possible haplotypes were analyzed. The high on-treatment platelet reactivity (HTPR) prevalence defined by a platelet inhibition rate <30% by TEG in adenosine diphosphate (ADP)-channel was 69 (38.33%). Six common haplotypes were inferred from four of the selected P2RY12 SNPs (denoted H0 to H5) according to the linkage disequilibrium R square (except for rs2046934). Haplotype H1 showed a significantly lower incidence of HTPR than the reference haplotype (H0) in the total study population while haplotypes H1 and H2 showed significantly lower incidences of HTPR than H0 in the nonsmoker subgroup after adjusting for CYP2C19 effects and demographic characteristics. rs2046934 (T744C) did not show any significant association with HTPR. The combination of common P2RY12 variations including regulatory regions rather than rs2046934 (T744C) that related to pharmacodynamics of clopidogrel in patients with ACS was independently associated with residual on-clopidogrel platelet reactivity. This is apart from the established association of the CYP2C19. This association seemed more important in the subgroup defined by smoking.

Relationship between pharmacokinetics and pharmacodynamics of clopidogrel in patients undergoing percutaneous coronary intervention: comparison between vasodilator‐stimulated phosphoprotein phosphorylation assay and multiple electrode aggregometry

ESSENTIALS: The reliability of platelet tests as markers of the variable bioavailability of clopidogrel is not yet defined. Kinetics of clopidogrel active metabolite (CAM) and platelet response were studied in ischemic heart disease. CAM plasma maximum concentration (Cmax ) predicted vasodilator-stimulated phosphoprotein (VASP-P). Timely performed VASP-P, not an aggregation-based test, may be a surrogate for clopidogrel bioavailability. The high inter-individual variability in the inhibition of platelet function by clopidogrel is mostly explained by high variability in its transformation to an active metabolite (CAM). Objective We investigated the relations between pharmacokinetics and pharmacodynamics of CAM by comparing two methods of platelet function. We enrolled 14 patients undergoing percutaneous coronary interventions for non-ST-segment elevation acute coronary syndrome or inducible myocardial ischemia. Plasma concentrations of clopidogrel and CAM, phosphorylation of vasodilator-stimulated phosphoprotein (VASP-P), expressed as a platelet reactivity index (PRI) and whole-blood platelet aggregation (multiple electrode aggregometer, MEA) were measured before and after a 600-mg clopidogrel loading dose (nine time-points) and before and after 75-mg maintenance doses on days 2, 7 and 30. Plasma concentrations of clopidogrel and CAM were highly variable. CAM reached maximal concentration (Cmax ) (median, 110.8 nm; range, 41.9-484.8) 0.5-2 h after the loading dose. A sigmoid dose-response curve defined the relations between CAMCmax and PRI after 3 to 24 h (IC50 , 459.6 nm; 95% confidence interval, 453.4-465.7; R(2) = 0.82). PRI was unchanged from baseline in patients with the lowest CAMCmax (< 83 nm, n = 7), indicating low sensitivity of VASP-P. PRI values were also predicted by CAMCmax at days 2, 7 and 30. Platelet aggregation measured by MEA did not show significant relations with either PRI or with CAM pharmacokinetics at any time-point. After 600 mg clopidogrel, VASP-P, but not whole-blood platelet aggregation measured by MEA, is almost entirely predicted by CAMCmax . VASP-P could be useful in studies aimed at investigating relations between CAM bioavailability and clinical events.

Effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of clopidogrel in rats

1. Fluvoxamine, a selective serotonin reuptake inhibitor (SSRI), is often coprescribed with clopidogrel for the treatment of ischemic vascular diseases. The aim of this study was to explore the effect of fluvoxamine on the pharmacokinetics and pharmacodynamics of clopidogrel.2. Twelve male rats were employed to investigate the effect of fluvoxamine on the pharmacokinetics of clopidogrel in vivo. Clopidogrel carboxylic acid was used for the pharmacokinetic study of clopidogrel.3. After pretreatment with high dose of fluvoxamine (27 mg/kg), there were significant increases in the AUC0 − t (from 9850 ± 4060 to 27 300 ± 6910 µg/l h; p < 0.05), AUC0 − ∞ (from 9850 ± 4060 to 27 600 ± 6800 µg/l h; p < 0.05) and t1/2 (from 2.07 ± 0.0942 to 7.49 ± 1.22 h; p < 0.05) of clopidogrel carboxylic acid. The pharmacokinetic data for clopidogrel carboxylic acid showed significant decreases in VLz/F (from 0.765 ± 0.299 to 0.256 ± 0.0594 l/kg; p < 0.05) after pretreatment with high dose of fluvoxamine. Pharmacodynamic studies that measure platelet aggregation percentage (from 21.63 ± 6.05% to 45.98 ± 5.11%; p < 0.01) show that high doses of fluvoxamine significantly inhibit the effect of clopidogrel.4. In conclusion, the pharmacokinetics and pharmacodynamics of clopidogrel were significantly affected by high doses of fluvoxamine. This study indicated that potential drug–drug interaction between fluvoxamine and clopidogrel should be taken into consideration in clinical use.

The impact of genetic polymorphisms of drug metabolizing enzymes on the pharmacodynamics of clopidogrel under steady state conditions

Clopidogrel is an antiplatelet drug that requires biotransformation steps to its active metabolite via cytochromes P450 (CYP), particularly CYP2C19 and CYP3A5 as well as paraoxonase-1 (PON1). The impact of CYP3A5 and PON1 genetic polymorphisms on the response of this drug is unclear. This study aimed to elucidate the degree of genetic polymorphisms of key drug metabolizing enzymes on the antiplatelet effect of clopidogrel. Thirty-five healthy subjects were treated with 75 mg/day clopidogrel for 7 days and serial blood samples were collected for measurement of antiplatelet effect using whole blood impedance aggregometry and VerifyNow® P2Y12 methods. The areas under the antiplatelet effect–time curves, maximal and minimal antiplatelet effects of clopidogrel obtained from both methods were significantly different among subjects with different CYP2C19 genotypes. In contrast, these pharmacodymamic parameters measured by both methods of subjects with different PON1 or CYP3A5 genotypes were not significantly different. Among the heterozygous CYP2C19*2 subjects, all pharmacodynamic parameters measured by whole blood impedance aggregometry were significantly different between subjects with different CYP3A5*3 genotypes. Our data suggests that CYP2C19 genetic polymorphism play a major role in the clopidogrel response, however, the impact of CYP3A5 genetic polymorphism, may be pronounced in the subjects who carried the loss-functional allele of CYP2C19.

Clinical pharmacokinetics and pharmacodynamics of clopidogrel.

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.

Genetic polymorphisms of CYP2C19*2 and ABCB1 C3435T affect the pharmacokinetic and pharmacodynamic responses to clopidogrel in 401 patients with acute coronary syndrome

Backgrounds and objectivesClopidogrel, an inhibitor of platelet ADP P2Y12 receptors, plays an important role in the prevention of stent thrombosis. However, some patients do not attain adequate antiplatelet effects. Studies have shown that the genetic variation in CYP2C19*2 is associated with an impaired response to clopidogrel. This study was designed to investigate the genetic variants of 21 genes involving in the absorption, metabolism, and pharmacodynamics of clopidogrel. The effects of these genes on the plasma level of clopidogrel and its metabolites (active clopi-H4 and inactive CLPM) and platelet reactivity were also studied. Methods and results401 acute coronary syndrome (ACS) patients received either a 300mg loading dose following 75mg maintenance dose daily or a 75mg maintenance dose daily of clopidogrel. The inhibition of platelets was assessed using light transmittance aggregometry. Plasma concentrations of clopidogrel as well as its active (clopi-H4) and inactive (CLPM) metabolites were measured using HPLC-MS-MS method. Among 21 genes, the carriers of CYP2C19*2 were associated with lower exposure to its active (clopi-H4) and inactive (CLPM) metabolites (both P<0.05 vs. non-carriers) and thus decreased platelet inhibition (P<0.05 vs. non-carriers). Notably, the carriers of ABCB1 C3435T were associated with lower levels of plasma clopidogrel and its active (clopi-H4) and inactive (CLPM) metabolites (all P<0.05 vs. non-carriers) which also correlated with subsequently decreased platelet inhibition (P<0.05 vs. non-carriers). There were no obvious effects of other studied genes on clopidogrel. ConclusionsCYP2C19*2 is a determinant for the formation of the active metabolite of clopidogrel and its antiplatelet effects. Meanwhile, ABCB1 C3435T plays an important role in intestinal absorption of clopidogrel which further affects the exposure to the active metabolite of clopidogrel and platelet aggregation.

Impact of common ABCB1 polymorphism on pharmacokinetics and pharmacodynamics of clopidogrel and its metabolites.

The reasons of clopidogrel (CLP) resistance are still unclear. The response to CLP may be influenced by both genetic and non-genetic factors. Among genetic factors, common polymorphisms in the gene coding glycoprotein-P (P-gp, MDR1 and ABCB1) are considered as potential determinants of the efficacy of CLP treatment. The aim of this study was to evaluate the influence of ABCB1 3435C>T genetic polymorphism on the pharmacokinetics and pharmacodynamics of CLP and its metabolites: diastereoisomers of thiol metabolite (the inactive H3 and the active H4) and inactive carboxylic derivative. The study group included 42 patients undergoing elective coronary angiography and percutaneous coronary intervention. The plasma concentrations of CLP and its metabolites were measured by a validated HPLC-MS/MS method. Whole-blood aggregation was determined with Multiplate analyzer. For evaluation of ABCB1 3435C>T polymorphism, PCR-RFLP method was applied. It was found that Exposition to the unchanged CLP, measured by AUC0-t of the drug, was significantly lower (P=0·012) in TT homozygotes comparing to that observed in CC and CT genotypes, although no correlation was found between platelet aggregation and ABCB1 genetic polymorphism. Our findings show that the presence of 3435C>T allele has an impact on CLP pharmacokinetics but not on the drug pharmacodynamics. Therefore, the 3435C>T genotype may not be the primary determinant influencing the pharmacokinetics of the active H4 metabolite and antiplatelet effect of the drug.