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Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis Patients.

2024; Elsevier BV; Volume: 9; Issue: 10 Linguagem: Inglês

10.1016/j.ekir.2024.07.029

2468-0249

Juergen Grafeneder, Wisse van Os, Iris K. Minichmayr, Katarina D. Kovacevic, Birgit Reiter, M. D. Saemann, Veronika Machold-Fabrizii, Amro Ahmed, Paul Spechtl, Haris Omić, Raute Sunder‐Plaßmann, Bernd Jilma, Christian Schoergenhofer, Farsad Eskandary,

Pharmacology and Obesity Treatment

IntroductionHemodialysis 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).MethodsWe 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.ResultsSeventeen 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.ConclusionOur 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.