Pharmacokinetics of clopidogrel in patients with stent thrombosis

Sibbing, Dirk; Taubert, Dirk; Schömig, Albert; Kastrati, Adnan; Beckerath, Nicolas von

doi:10.1111/j.1538-7836.2008.03004.x

Cited by 11 publications

(11 citation statements)

References 19 publications

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“…Sibbing et al. [31] reported diminished conversion of clopidogrel into its active thiol metabolite in patients with a history of stent thrombosis following percutaneous coronary intervention. This was reflected by a significantly lower C max of CTM in patients (3.2 ng/mL) than in healthy control subjects (14.5 ng/mL) following administration of clopidogrel 600 mg. A similar conclusion may be drawn from the results of the present study, where the C max values of the H3 and H4 isomers of CTM were 5.29 and 7.13 ng/mL, respectively (Table 2), and were lower than those reported in healthy volunteers, according to the literature data.…”

Section: Discussionmentioning

confidence: 99%

Clinical Pharmacokinetics of Clopidogrel and Its Metabolites in Patients with Cardiovascular Diseases

et al. 2013

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Background and ObjectiveApproximately 5–40 % of patients treated with clopidogrel do not display an adequate antiplatelet response. Clopidogrel resistance may be caused by insufficient drug absorption or impaired metabolic activation of the drug. The aim of this study was to evaluate the pharmacokinetics of clopidogrel and its metabolites in plasma samples from patients treated with high and low doses of clopidogrel, to obtain a possible explanation for antiplatelet resistance.MethodsThe study included patients receiving either a single 300 mg loading dose of clopidogrel (n = 17) or a 75 mg dose (n = 45) for at least 7 days before sample collection. The concentrations of clopidogrel and its metabolites—the inactive H3 and the pharmacologically active H4 isomers of the thiol metabolite and the inactive carboxylic acid metabolite—in plasma samples (stabilized with 2-bromo-3′-methoxyacetophenone) from three patients after 300 mg and from 41 patients after 75 mg of the drug were determined using a validated high-performance liquid chromatography method with tandem mass spectrometry. The non-stabilized samples from the remaining patients were analysed using a validated capillary electrophoresis method. The calculated concentrations were used to determine the pharmacokinetic parameters of the analytes. The pharmacodynamic response to clopidogrel treatment, expressed as adenosine diphosphate-induced platelet aggregation, was measured using a Multiplate analyser.ResultsThe pharmacokinetic parameter values for the H3 and H4 isomers determined in the studied group of patients treated with clopidogrel 75 mg (maximum plasma concentration [Cmax] 5.29 ± 5.54 and 7.13 ± 6.32 ng/mL for H3 and H4, respectively; area under the plasma concentration-time curve from time zero to time t [AUCt] 7.37 ± 6.71 and 11.30 ± 9.58 ng·h/mL for H3 and H4, respectively) were lower than those reported in healthy volunteers, according to the literature data. Platelet aggregation measured with a Multiplate analyser ranged between 37 and 747 AU·min. A significant correlation was found between the Cmax of the active H4 isomer and platelet aggregation (p = 0.025).ConclusionThe Cmax of the active H4 isomer and platelet aggregation measured by the Multiplate analyser may serve as markers of the patient response to clopidogrel therapy.

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Section: Discussionmentioning

confidence: 99%

Clinical Pharmacokinetics of Clopidogrel and Its Metabolites in Patients with Cardiovascular Diseases

et al. 2013

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“…23 The result of the present meta-analysis supports the findings of previous studies, showing that the conversion of clopidogrel into its active compound is significantly decreased in patients with stent thrombosis when compared with healthy controls. 24 The presence of the CYP2C19*2 allele is, Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in fact, able to determine an altered metabolism of clopidogrel, thus possibly increasing the risk of stent thrombosis in the follow-up period after percutaneous coronary intervention with stent implantation. Moreover, stent thrombosis is more likely to be affected by the inadequate deactivation of the platelet activity determined by the CYP2C19*2 polymorphism, with respect to the combined endpoint, including fatal and non-fatal myocardial infarction, unstable angina, stroke and deaths from any causes, whose pathogenetic mechanisms are more intricate.…”

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis

et al. 2010

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“…No. DE 10 2004 046 159.7) [14] in order to prevent degradation of the AMC. After vortexing for 60 s, samples were stored at )80°C until analysis of the AMC plasma concentration with liquid chromatography-tandem mass spectrometry (LC-MS/MS).…”

Section: Study Protocol and Blood Samplingmentioning

confidence: 99%

Which platelet function test is suitable to monitor clopidogrel responsiveness? A pharmacokinetic analysis on the active metabolite of clopidogrel

Bouman

Parlak

Werkum

et al. 2010

Journal of Thrombosis and Haemostasis

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102

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is suitable to monitor clopidogrel responsiveness? A pharmacokinetic analysis on the active metabolite of clopidogrel. J Thromb Haemost 2010; 8: 482-8.Summary. Background: Multiple platelet function tests claim to be P2Y12-pathway specific and capable of capturing the biological activity of clopidogrel. Objectives: The aim of the present study was to determine which platelet function test provides the best reflection of the in vivo plasma levels of the active metabolite of clopidogrel (AMC). Patients/methods: Clopidogrel-naive patients scheduled for elective percutaneous coronary intervention (PCI) received a 600 mg loading dose of clopidogrel and 100 mg of aspirin. For pharmacokinetic analysis, blood was drawn at 0,20, 40, 60, 90, 120, 180, 240 and 360 min after clopidogrel loading and peak plasma concentrations (C max ) of the AMC were quantified with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Platelet function testing was performed at baseline and 360 min after the clopidogrel loading. Results: The VASP-assay, the VerifyNow P2Y12-assay and 20 lmol L )1 adenosine diphosphate (ADP)-induced light transmittance aggregometry (LTA) showed strong correlations with C max of the AMC (VASP: R 2 = 0.56, P < 0.001; VerifyNow platelet reactivity units (PRU): R 2 = 0.48, P < 0.001; VerifyNow %inhibition:R 2 = 0.47, P < 0.001). Agreement with C max of the AMC was less evident for 5 lmol L )1 ADP-induced LTA or whole blood aggregometry (WBA), whereas the IMPACT-R ADP test did not show any correlation with plasmalevels of the AMC. Conclusion:The flow cytometric VASP-assay, the VerifyNow P2Y12 assay and, although to a lesser extent, 20 lmol L )1 ADPinduced LTA correlate best with the maximal plasma level of the AMC, suggesting these may be the preferred platelet function tests for monitoring the responsiveness to clopidogrel.

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Pharmacokinetics of clopidogrel in patients with stent thrombosis

Cited by 11 publications

References 19 publications

Clinical Pharmacokinetics of Clopidogrel and Its Metabolites in Patients with Cardiovascular Diseases

Clinical Pharmacokinetics of Clopidogrel and Its Metabolites in Patients with Cardiovascular Diseases

Cytochrome P450 2C19*2 polymorphism and cardiovascular recurrences in patients taking clopidogrel: a meta-analysis

Which platelet function test is suitable to monitor clopidogrel responsiveness? A pharmacokinetic analysis on the active metabolite of clopidogrel

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