Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis Patients
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 pros...
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Elsevier
2024-10-01
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| Series: | Kidney International Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S246802492401859X |
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| author | Juergen Grafeneder Wisse van Os Iris K. Minichmayr Katarina D. Kovacevic Miljevic Birgit Reiter Marcus D. Säemann Veronika Machold-Fabrizii Amro Ahmed Paul Spechtl Haris Omic Raute Sunder-Plaßmann Bernd Jilma Christian Schoergenhofer Farsad Eskandary |
| author_facet | Juergen Grafeneder Wisse van Os Iris K. Minichmayr Katarina D. Kovacevic Miljevic Birgit Reiter Marcus D. Säemann Veronika Machold-Fabrizii Amro Ahmed Paul Spechtl Haris Omic Raute Sunder-Plaßmann Bernd Jilma Christian Schoergenhofer Farsad Eskandary |
| author_sort | Juergen Grafeneder |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8058fc35fec6452286b842b4e9bd2c29 |
| institution | OA Journals |
| issn | 2468-0249 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Elsevier |
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| series | Kidney International Reports |
| spelling | doaj-art-8058fc35fec6452286b842b4e9bd2c292025-08-20T02:06:15ZengElsevierKidney International Reports2468-02492024-10-019102970298010.1016/j.ekir.2024.07.029Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis PatientsJuergen Grafeneder0Wisse van Os1Iris K. Minichmayr2Katarina D. Kovacevic Miljevic3Birgit Reiter4Marcus D. Säemann5Veronika Machold-Fabrizii6Amro Ahmed7Paul Spechtl8Haris Omic9Raute Sunder-Plaßmann10Bernd Jilma11Christian Schoergenhofer12Farsad Eskandary13Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Department of Emergency Medicine, Medical University of Vienna, Vienna, AustriaDepartment of Clinical Pharmacology, Medical University of Vienna, Vienna, AustriaDepartment of Clinical Pharmacology, Medical University of Vienna, Vienna, AustriaDepartment of Clinical Pharmacology, Medical University of Vienna, Vienna, AustriaDepartment of Laboratory Medicine, Medical University of Vienna, Vienna, Austria6th Medical Department, Nephrology and Dialysis, Clinic Ottakring, Vienna, Austria6th Medical Department, Nephrology and Dialysis, Clinic Ottakring, Vienna, Austria3rd Medical Department, Cardiology and Intensive Care Medicine, Clinic Ottakring, Vienna, AustriaDepartment of Nephrology and Dialysis, Division of Medicine III, Medical University of Vienna, Vienna, AustriaDepartment of Nephrology and Dialysis, Division of Medicine III, Medical University of Vienna, Vienna, AustriaDepartment of Laboratory Medicine, Medical University of Vienna, Vienna, AustriaDepartment of Clinical Pharmacology, Medical University of Vienna, Vienna, AustriaDepartment of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Correspondence: Christian Schoergenhofer, Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, AustriaDepartment of Nephrology and Dialysis, Division of Medicine III, Medical University of Vienna, Vienna, Austria; Farsad Eskandary, Division of Medicine III, Department of Nephrology and Dialysis, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria.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.http://www.sciencedirect.com/science/article/pii/S246802492401859Xcardiovascular riskclopidogrelcytochrome P450hemodialysispharmacokineticsplatelet aggregation |
| spellingShingle | Juergen Grafeneder Wisse van Os Iris K. Minichmayr Katarina D. Kovacevic Miljevic Birgit Reiter Marcus D. Säemann Veronika Machold-Fabrizii Amro Ahmed Paul Spechtl Haris Omic Raute Sunder-Plaßmann Bernd Jilma Christian Schoergenhofer Farsad Eskandary Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis Patients Kidney International Reports cardiovascular risk clopidogrel cytochrome P450 hemodialysis pharmacokinetics platelet aggregation |
| title | Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis Patients |
| title_full | Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis Patients |
| title_fullStr | Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis Patients |
| title_full_unstemmed | Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis Patients |
| title_short | Prospective Trial on the Pharmacokinetics of Clopidogrel in Hemodialysis Patients |
| title_sort | prospective trial on the pharmacokinetics of clopidogrel in hemodialysis patients |
| topic | cardiovascular risk clopidogrel cytochrome P450 hemodialysis pharmacokinetics platelet aggregation |
| url | http://www.sciencedirect.com/science/article/pii/S246802492401859X |
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