Abstract

Clopidogrel is an oral antiplatelet drug. Loading dose of 600 mg clopidogrel was shown to improve clinical outcome in patients following percutaneous coronary intervention (PCI). Wide inter-individual variation has been detected in clopidogrel response that can be related to variation in Clopidogrel serum concentration. The aim of this study was to assess the pharmacokinetics parameters of 600 mg loading dose clopidogrel among Jordanian patients undergoing PCI. Additionally, the development of a simple and a validated High-performance liquid chromatography (HPLC) method for the quantification of clopidogrel carboxylate was described. 80 patients who received a loading of 600 mg Clopidogrel were included in our study, several blood samples were collected at different time points. Validated reverse phase HPLC method was used to determine Clopidogrel carboxylic acid metabolite. Non-compartmental analysis was used to determine peak plasma concentration (C_max), time to peak plasma concentration (T_max), elimination half-life (t_1/2e), and area under the curve (AUC). The pharmacokinetic-parameters were characterized by considerable inter-individual differences [C_max=24.49±11.64 µg/ml, T_max=2.02±1.52 h, AUC_0→∞= 123.17± 54.6 mg/ml.h, and t1 ⁄ 2e=4.29±2.92 h]. 15% of the patients who had less than one third of the _Cmax 8.09±2.34 µg/ml had delayed T_max of 4.17±1.76 h, which was not explained by standard in vitro dissolution test. Pharmacokinetic parameters of 600 mg Clopidogrel showed marked inter-individual differences. The low plasma concentrations in some of the patients and the high inter-individual variability may contribute to reported cases of resistance to Clopidogrel therapy. Further studies are needed to explain low C_max and delayed T_max values in some patients.

Key words:    Clopidogrel carboxylic acid, loading dose, percutaneous coronary intervention, reverse phase High-performance liquid chromatography (HPLC), pharmacokinetics.

Abbreviation

ADP, Adenosine diphosphate; P₂Y₁₂, platelet receptor; C_max, maximum plasma concentration; AUC_0®∞, area under the “plasma concentration vs. time” curve; BMI,body mass index; Hb, hemoglobin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; T_max, time to peak plasma concentration; C_last, last quantifiable concentration; t_1/2e, elimination half life; AUMC, area under the first momentum curve; MRT,mean residence time; Vd, apparent volume of distribution; D, accepted margin of error; SD,standard deviation; CV, coefficient of variation.