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Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis Patients
Juergen Grafeneder1,2, Wisse van Os1, Iris K Minichmayr1
1Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Insights
Hemodialysis patients have impaired clopidogrel metabolism, leading to lower active metabolite levels and increased platelet aggregation. This suggests reduced effectiveness of clopidogrel in this population.
Area of Science:
- Pharmacology
- Nephrology
- Cardiovascular Medicine
Background:
- Hemodialysis patients (HDPs) face significant cardiovascular risks.
- Clopidogrel, an antiplatelet drug, requires metabolic activation by cytochrome enzymes.
- Uremia and inflammation in HDPs may impair this activation process.
Purpose of the Study:
- To investigate the pharmacokinetics and pharmacodynamics of clopidogrel in HDPs compared to healthy volunteers (HVs).
- To assess the impact of hemodialysis on clopidogrel's metabolic activation and antiplatelet effects.
Main Methods:
- Prospective multicenter study comparing HDPs on clopidogrel and pantoprazole with HVs.
- Quantification of plasma concentrations using mass spectrometry.
- Assessment of platelet aggregation via adenosine diphosphate-induced whole-blood aggregometry.
Main Results:
- HDPs showed significantly lower maximum concentrations of clopidogrel's active metabolite compared to HVs.
- Population pharmacokinetic modeling revealed an 82.7% reduced clopidogrel clearance in HDPs.
- Platelet aggregation was significantly higher in HDPs, indicating reduced clopidogrel efficacy.
Conclusions:
- Clopidogrel metabolism is altered in HDPs, associated with reduced CYP2C19 activity.
- This impaired metabolism may affect the efficacy of clopidogrel in preventing cardiovascular events in HDPs.
- Findings suggest potential implications for other drugs metabolized by CYP2C19 in this patient group.
Introduction:
Hemodialysis patients (HDPs) 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 HDPs. We conducted a prospective multicenter study to investigate the pharmacokinetics and pharmacodynamics of clopidogrel in HDPs and healthy volunteers (HVs).
Methods:
We enrolled HDPs receiving long-term clopidogrel (75 mg) and pantoprazole treatment (40 mg). Healthy volunteers 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. Platelet aggregation was measured using adenosine diphosphate-induced whole-blood aggregometry.
Results:
Seventeen HDPs and 16 HVs were included. The maximum concentration of clopidogrel's active metabolite was significantly lower in HDPs compared to HVs (median [interquartile range] 12.2 [4.6-23.4] vs. 24.7 [17.8-36.5] ng/ml, P = 0.02). The maximum concentration ratio of clopidogrel's active metabolite to prodrug was 8.5-fold lower in HDPs, and an 82.7% reduced clopidogrel clearance, including clopidogrel's active metabolite formation, was found using population pharmacokinetic modeling. From previous studies, adenosine diphosphate-induced platelet aggregation at 120 minutes was significantly higher in HDPs than in HVs (median [interquartile range]: 26 U [14 U-43 U] vs. 12 U [11 U-18 U], P = 0.004. Pantoprazole terminal half-life was ∼1.7-fold higher in HDPs compared to HVs.
Conclusion:
Our data demonstrate an altered metabolism of clopidogrel in HDPs in the context of lower CYP2C19 activity, with potential implications for other substances metabolized by this enzyme.
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