Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis Patients

Abstract

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.

Keywords: cardiovascular risk; clopidogrel; cytochrome P450; hemodialysis; pharmacokinetics; platelet aggregation.

Graphical abstract

Figure 1

Concentration of clopidogrel as prodrug (a) and its active metabolite (b) over time. Data are presented as the median and the interquartile range. HDP, hemodialysis patients; HV, healthy volunteers.

Figure 2

Concentration of the clopidogrel prodrug (a) and the active metabolite (CAM; b). (c) The ratio between CAM and prodrug can be seen. Horizontal lines represent the median and the interquartile range. CAM, active metabolite of clopidogrel; Cmax, maximum concentration; HDP, hemodialysis patients; HV, healthy volunteers; IQR, interquartile range;

Figure 3

Results for Multiplate assay (ADP-induced aggregation) and VASP assay (Platelet-reactivity index, PRI) over time (a, c). Individual data are shown at 120 min (b, d). Data are presented as median and interquartile range. The dotted lines in b and d represent the HTPR cutoff (>46 U for ADP and > 50% for VASP). ∗∗P < 0.01; ADP, adenosine diphosphate; HDP, hemodialysis patients; HTPR, high on-treatment platelet reactivity; HV, healthy volunteers; PRI, platelet reactivity index; VASP, vasodilator-associated stimulated phosphoprotein;