Cirrhosis does not affect the pharmacokinetics and pharmacodynamics of clopidogrel.
Clopidogrel, a new platelet ADP receptor antagonist used for the prevention of vascular ischemic events, is converted to an active metabolite via the cytochrome P450 system. Patients with cirrhosis may not metabolize drugs normally and may, in addition, have a number of defects in the coagulation system. To assess the effect of cirrhosis on the pharmacokinetics and pharmacodynamics of clopidogrel, the authors performed an open-label, parallel-group study of 12 patients with Child-Pugh Class A or B cirrhosis and 12 matched controls. All 24 subjects received clopidogrel 75 mg PO QD for 10 days. Pharmacokinetics of clopidogrel and the major metabolite SR 26334 were analyzed on Days 1 and 10; pharmacodynamics were assessed by the inhibition of ADP-induced platelet aggregation and by bleeding time prolongation factor. Pharmacokinetic analysis of clopidogrel was limited due to low plasma concentrations arising from rapid hydrolysis to SR 26334. The Cmax at SS for clopidogrel was higher in cirrhotics than in normals. However, exposures to the metabolite SR 26334, as measured by AUC(tau), were comparable. At Day 10, there was not a statistically significant difference in mean inhibition of platelet aggregation (49.2% +/- 38.6% in cirrhotics vs. 66.7% +/- 7.5% in normals) or in bleeding time prolongation factor (1.64 +/- 0.49 in cirrhotics vs. 1.54 +/- 0.87 in normals) between groups. No significant adverse events, including bleeding events, were reported. In conclusion, there were no significant differences in the pharmacokinetics and pharmacodynamics of clopidogrel in this group of subjects with cirrhosis and matched normals. Therefore, no dosage adjustment of clopidogrel is required in patients with Child-Pugh Class A or B cirrhosis.
Slugg
P H
PH
Department of Clinical Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Much
D R
DR
Smith
W B
WB
Vargas
R
R
Nichola
P
P
Necciari
J
J
D000328:Adult; D019540:Area Under Curve; D016022:Case-Control Studies; D000077144:Clopidogrel; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D012871:Skin Diseases / Q000139:chemically induced; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D013997:Time Factors
D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine