19 Andrzej Budaj Grochowski Hospital, Warsaw, Poland Clopidogrel (CLP), since its first approval in 1997, has been the most prescribed and studied medication as percutaneous coronary intervention (PCI) became the dominant approach for myocardial revascularization. Clopidogrel bisulfate, the thienopyridine, irreversibly inhibits the P2Y12 adenosine diphosphate platelet receptor. Clopidogrel is metabolized in the liver via two competing pathways. In one, about 85% of absorbed CLP is hydrolyzed by carboxylesterase-1 to an inactive carboxylic acid metabolite. In the second, CLP is converted to the active metabolite (15%) in a two-step oxidative reaction catalyzed by cytochrome P450 (CYP450). In the first step, CLP is oxidized to the thiolactone derivative (2-oxo-clopidogrel) by CYP1A2, CYP2B6, and CYP2C19. Subsequently, from thiolactone, an active thiol metabolite is formed by a hydraulic cleavage of the γ-thiobutyrolactone ring. CYP2B6, CYP2C9, CYP2C19, and CYP3A4 are involved in this reaction [1]. Active metabolite is a highly labile compound that through a disulfate bridge binds irreversibly with cysteine on platelet P2Y12 receptor [2]. A recently published study has suggested that paraoxonase-1, a Ca+-dependent esterase that inhibits oxidative modification of LDL cholesterol, might play a role in the bioactivation of CLP [3]. However, subsequent studies have failed to reproduce this finding [4]. In the study with healthy volunteers, CLP in doses 300–400 mg produced a rapid onset of the pharmacodynamic action, with levels of platelet aggregation inhibition close to steady state reached within 2 h [5]. However, in a study of patients with stable coronary artery disease, only 16% of patients were observed to reach over 70% inhibition of platelet aggregation by 2 h after 600 mg of CLP loading dose (LD) [6]. Inhibition of platelet aggregation was higher with 600 and 900 mg than 300 mg LD [7]. These results suggest a variability of platelet response to CLP. About 50% of an orally administered dose of CLP is absorbed from the gastrointestinal tract. It has been demonstrated that CLP absorption in the intestine was diminished by active secretion via efflux pump P-glycoprotein (P-gp) encoded by the gene MDR1 (ABCB1) [8]. This mechanism is suggested as potentially diminishing the substrate for active metabolite of CLP [2]. The active metabolite of CLP is highly unstable and its pharmacokinetics have been only recently determined. Due to rapid and extensive metabolism in the liver, plasma concentrations of the parent compound are generally below the level of the detection beyond 2 h after administration of CLP 75 mg/day. Therefore, the pharmacokinetics of CLP have been characterized by evaluating the main circulating metabolite, the carboxylic acid derivative. In order to evaluate compliance to CLP therapy, it may be appropriate to measure the main inactive metabolite since it can be tracked for 24–48 h after cessation of therapy [9]. However, a number of analytical methods have been elaborated to measure the parent drug, CLP, and its active compound [10]. After an oral single-dose administration of CLP 75 mg to healthy volunteers, a mean peak plasma concentration (Cmax) of 2.8 mg/L for the carboxylic acid metabolite was achieved after 0.8 h [11]. The administration of various LDs in patients with stable CAD treated with PCI has been elaborated. Loading with 600 mg resulted in higher plasma concentrations of active metabolite, CLP, and carboxyl metabolite compared with loading with 300 mg. With administration of 900 mg, no further increase in plasma concentrations of active metabolite and CLP was achieved. Peak concentrations of each compound with administered LDs occurred within 40–60 min [7]. Both the parent and active metabolite are highly protein bound (>94%). Following oral administration of 14C-clopidogrel, approximately 50% and 46% of the drug was excreted in the urine and feces, respectively [12]. Clopidogrel has undergone extensive evaluation in several large, randomized, double-blind clinical trials that have, collectively, included over 100,000 patients. The studies have shown that CLP, either alone or added to aspirin (ASA), is superior to ASA monotherapy in reducing clinical end points (see Table 19.1 for efficacy results from selected major CLP trials). The CURE trial revealed a 20% relative risk reduction in the first coprimary end point and 14% relative risk reduction of the second coprimary end point (first primary end point or refractory ischemia). The benefits of CLP in preventing the first coprimary outcomes were evident at 30 days and were maintained to the end of the trial. Risk reduction in ischemic vascular events emerged within 24 h after starting treatment [13]. Subgroup analyses showed that the benefits of CLP were consistent in low-, intermediate-, and high-risk groups according to the Thrombolysis in Myocardial Infarction (TIMI) Risk Score [18]. Table 19.1 Efficacy of CLP in major trials with reperfusion therapy.
Clopidogrel
Pharmacodynamic properties
Pharmacokinetic properties
Therapeutic use
Trial
Treatments
Primary end points
Follow-up
Primary end point results % (p-value)
CURE [13]
CLP 300 mg LD, then 75 mg/day versus ASA alone
CV death, MI, or stroke
3–12 months
9.3 versus 11.4 (<0.001) Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
Get Clinical Tree app for offline access