Comparative bioavailability of two oral formulations of clopidogrel: Determination of clopidogrel and its carboxylic acid metabolite (SR26334) under fasting and fed conditions in healthy subjects

Abstract

Clopidogrel, a thienopyridine derivative, is a potent antiplatelet drug that inhibits adenosine diphosphate (ADP)-mediated platelet activation and aggregation by selectively and irreversibly binding to platelet P2Y 12 purinergic receptor (1). Results of a large clinical trial have demonstrated an overall benefit of clopidogrel over aspirin in the prevention of vascular ischemic events (myocardial infarction, stroke, vascular death) in patients with a history of symptomatic atherosclerotic disease (2). However, platelet inhibition by clopidogrel is highly variable, and patients with reduced platelet inhibition have an increased risk of major cardiovascular events (3, 4). Two randomized, single dose, 2-period, 2-sequence crossover studies were conducted to evaluate the comparative bioavailability of two clopidogrel formulations under fasting and fed conditions. Assessment of bioequivalence was based upon measurement of plasma concentrations of the parent drug, clopidogrel, and its major (inactive) metabolite, clopidogrel carboxylic acid, using improved methanol-free extraction. Bioequivalence of Krka's formulation to the innovator's formulation was demonstrated under both fasting and fed conditions on 205 volunteers. Confidence intervals for AUC 0-t , AUC 0-inf and C max of clopidogrel and its main metabolite were well within the acceptance range of 80.00 to 125.00 %. Food substantially increased the bioavailability of clopidogrel from both formulations, while no effect of food on the extent and rate of exposure to the metabolite was observed. The effect of food was comparable between the two formulations, as indicated by the same direction and rank of food impact on the bioavailability of both formulations.

Evaluation of potential drug interactions with sodium zirconium cyclosilicate: a single-center, open-label, one sequence crossover study in healthy adults

“…The observed decreases in the clopidogrel acid AUC 0– t and AUC inf , as well as the delayed t max , are consistent with reduced clopidogrel solubility and a slight decrease in absorption caused by increased gastric pH with SZC. A previous study observed similar changes when clopidogrel was administered with food [ 30 ]. In fed versus fasted studies, clopidogrel acid C max decreased by 10–16% without altering the antiplatelet activity of clopidogrel [ 30 ].…”

“…A previous study observed similar changes when clopidogrel was administered with food [ 30 ]. In fed versus fasted studies, clopidogrel acid C max decreased by 10–16% without altering the antiplatelet activity of clopidogrel [ 30 ]. During coadministration of clopidogrel with PPIs that do not inhibit cytochrome P450 (e.g.…”

Comparative fasting bioavailability of two clopidogrel formulations in healthy Mediterranean volunteers: an in vitro–in vivo correlation

“…Several previous studies have tested the bioequivalence of new generic clopidogrel against Plavix ® tablets 3 , 17 , 18 or the antiplatelet effect of other salts. 5 , 19 The aim of this study was to test the bioavailability of new generic clopidogrel 75 mg tablet versus the reference Plavix.…”

Physiologically Based Pharmacokinetic (PBPK) Modeling of Clopidogrel and Its Four Relevant Metabolites for CYP2B6, CYP2C8, CYP2C19, and CYP3A4 Drug–Drug–Gene Interaction Predictions

“…All studies were conducted in healthy participants covering a wide dosing range, SD and MD, intravenous and peroral administration. Considering the digitized studies, training [ 23 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ] and test datasets [ 42 , 44 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ] were defined for development and evaluation of the clopidogrel model, respectively. The training dataset preferably included profiles reporting many measurement points over a long period of time and studies quantifying multiple metabolites of interest.…”