Clopidogrel (Page 5 of 8)

12.3 Pharmacokinetics

Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.

Absorption

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Effect of Food

Clopidogrel bisulfate can be administered with or without food. In a study in healthy male subjects when clopidogrel bisulfate 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC 0–24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite C max . Similar results were observed when a clopidogrel bisulfate 300 mg loading dose was administered with a high-fat breakfast.

Metabolism

Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxoclopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.

The C max of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. C max occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: 4-fold the dose results in 2.0-fold and 2.7-fold the C max and AUC, respectively.

Elimination

Following an oral dose of 14 C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.

Drug Interactions

Effect of other drugs on Clopidogrel Bisulfate

Clopidogrel is metabolized to its active metabolite in part by CYP2C19.

CYP2C19 inducers

Concomitant use of strong inducers of CYP2C19 results in increased plasma concentration of the active metabolite of clopidogrel and an increase in platelet inhibition.

Rifampin: Coadministration of rifampin 300 mg twice daily for 7 days with 600 mg loading dose of clopidogrel in healthy adults increased the mean AUC and Cmax of clopidogrel’s thiol metabolites by 3.8-fold. Mean inhibition of platelet aggregation at 4 hours post-dose was 34% higher in the presence of rifampin compared to clopidogrel administered alone.

CYP2C19 inhibitors

Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

Proton pump inhibitors (PPI)

The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel bisulfate 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1.

Figure 1: Exposure to Clopidogrel Active Metabolite Following Multiple Doses of Clopidogrel Bisulfate 75 mg Alone or with Proton Pump Inhibitors (PPIs)

                                                        Change relative to clopidogrel bisulfate administered alone
(click image for full-size original)

Change relative to clopidogrel bisulfate administered alone

Pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction was highest with omeprazole and least with dexlansoprazole.

Opioids

Co-administration of 5 mg intravenous morphine with 600 mg loading dose of clopidogrel in healthy adults decreased the AUC and C max of clopidogrel’s thiol metabolites by 34%. Mean platelet aggregation was higher up to 2 to 4 hours with morphine co-administration.

Effect of Clopidogrel Bisulfate on other drugs

In vitro studies have shown that the glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Concomitant administration of repaglinide with clopidogrel bisulfate increased the systemic exposure to repaglinide (AUC 0-∞ ) by 5.1-fold following the loading dose (300 mg) and by 3.9-fold on day 3 of the maintenance dose (75 mg) of clopidogrel bisulfate [see Drug Interactions (7.6)].

12.5 Pharmacogenomics

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. Patients who are homozygous for nonfunctional alleles of the CYP2C19 gene are termed “CYP2C19 poor metabolizers”. Approximately 2% of White and 4% of Black patients are poor metabolizers; the prevalence of poor metabolism is higher in Asian patients (e.g., 14% of Chinese). Tests are available to identify patients who are CYP2C19 poor metabolizers.

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups.

Table 3: Active Metabolite Pharmacokinetics and Antiplatelet Responses by CYP2C19 Metabolizer Status
Dose Poor (n=10) Intermediate* (n=10) Normal (n=10) Ultrarapid (n=10)
Values are mean (SD) *Intermediate metabolizers have one but not two nonfunctional alleles Ultrarapid metabolizers have at least one gain-of-function allele Inhibition of platelet aggregation with 5mcM ADP; larger value indicates greater platelet inhibition § Vasodilator-stimulated phosphoprotein – platelet reactivity index; smaller value indicates greater platelet inhibition Values are mean (SD).
C max (ng/mL) 300 mg (24 h) 11 (4) 23 (11) 32 (21) 24 (10)
600 mg (24 h) 17 (6) 39 (23) 44 (27) 36 (13)
75 mg (Day 5) 4 (1) 12 (5) 13 (7) 12 (6)
150 mg (Day 5) 7 (2) 18 (7) 19 (5) 16 (9)
IPA (%) 300 mg (24 h) 24 (26) 37 (21) 39 (28) 40 (21)
600 mg (24 h) 32 (25) 56 (22) 49 (23) 51 (28)
75 mg (Day 5) 37 (23) 60 (18) 58 (19) 56 (13)
150 mg (Day 5) 61 (14) 74 (14) 73 (9) 68 (18)
VASP-PRI (%) § 300 mg (24 h) 91 (12) 78 (12) 68 (16) 73 (12)
600 mg (24 h) 85 (14) 56 (26) 48 (20) 51 (20)
75 mg (Day 5) 83 (13) 50 (16) 39 (14) 40 (9)
150 mg (Day 5) 61 (18) 29 (11) 24 (10) 20 (10)

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