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.