Clopidogrel Bisulfate (Page 4 of 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)
C max (ng/mL) 300 mg (24 h) 600 mg (24 h) 75 mg (Day 5) 150 mg (Day 5) 11 (4) 17 (6) 4 (1) 7 (2) 23 (11) 39 (23) 12 (5) 18 (7) 32 (21) 44 (27) 13 (7) 19 (5) 24 (10) 36 (13) 12 (6) 16 (9)
IPA (%) 300 mg (24 h) 600 mg (24 h) 75 mg (Day 5) 150 mg (Day 5) 24 (26) 32 (25) 37 (23) 61 (14) 37 (21) 56 (22) 60 (18) 74 (14) 39 (28) 49 (23) 58 (19) 73 (9) 40 (21) 51 (28) 56 (13) 68 (18)
VASP-PRI (%) § 300 mg (24 h) 600 mg (24 h) 75 mg (Day 5) 150 mg (Day 5) 91 (12) 85 (14) 83 (13) 61 (18) 78 (12) 56 (26) 50 (16) 29 (11) 68 (16) 48 (20) 39 (14) 24 (10) 73 (12) 51 (20) 40 (9) 20 (10)
*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).

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures >25 times that in humans at the recommended daily dose of 75 mg.

Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).

Clopidogrel was found to have no effect on fertility of male and female rats treated prior to pairing and throughout gestation at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m 2 basis).

14 CLINICAL STUDIES

14.1 Acute Coronary Syndrome

CURE

The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal.

Patients were randomized to receive clopidogrel (300 mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75 to 325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.

The patient population was largely White (82%) and included 38% women, and 52% age ≥ 65 years of age. Only about 20% of patients underwent revascularization during the initial hospitalization and few underwent emergent or urgent revascularization.

The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10% to 28%; p < 0.001) for the clopidogrel-treated group (see Table 4).

Table 4: Outcome Events in the CURE Primary Analysis
OutcomeClopidogrel (+ aspirin) *(n=6259) Placebo (+ aspirin) *(n=6303) Relative Risk Reduction (%) (95% CI)
*
Other standard therapies were used as appropriate.
The individual components do not represent a breakdown of the primary and co-primary outcomes, but rather the total number of subjects experiencing an event during the course of the study.
Primary outcome (Cardiovascular death, MI, stroke) 582 (9.3%)719 (11.4%)20% (10.3, 27.9) p < 0.001
All Individual Outcome Events:
CV death 318 (5.1%)345 (5.5%)7% (-7.7, 20.6)
MI324 (5.2%)419 (6.6%)23% (11.0, 33.4)
Stroke75 (1.2%)87 (1.4%)14% (-17.7, 36.6)

Most of the benefit of clopidogrel occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months) (see Figure 2).

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The effect of clopidogrel did not differ significantly in various subgroups, as shown in Figure 3. The benefits associated with clopidogrel were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE inhibitors. The efficacy of clopidogrel was observed independently of the dose of aspirin (75 to 325 mg once daily). The use of oral anticoagulants, nonstudy antiplatelet drugs, and chronic NSAIDs was not allowed in CURE.

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The use of clopidogrel in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the clopidogrel group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of clopidogrel in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting) (2,253 patients [36.0%] in the clopidogrel group, 2,324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).

COMMIT

In patients with STEMI, the safety and efficacy of clopidogrel were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities ( i.e. , ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive clopidogrel (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first.

The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.

The patient population was 28% women and 58% age ≥ 60 years (26% age ≥ 70 years). Fifty- five percent (55%) of patients received thrombolytics and only 3% underwent PCI.

As shown in Table 5 and Figure 4 and Figure 5 below, clopidogrel significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p=0.002).

Table 5: Outcome Events in COMMIT

Event Clopidogrel (+ aspirin) (N=22961) Placebo (+ aspirin) (N=22891) Odds ratio (95% CI) p-value
Composite endpoint: Death, MI, or Stroke* 2121 (9.2%)2310 (10.1%)0.91 (0.86, 0.97)0.002
Death Non-fatal MI Non-fatal Stroke 1726 (7.5%) 270 (1.2%) 127 (0.6%) 1845 (8.1%) 330 (1.4%) 142 (0.6%) 0.93 (0.87, 0.99) 0.81 (0.69, 0.95) 0.89 (0.70, 1.13) 0.029 0.011 0.33

*9 patients (2 clopidogrel and 7 placebo) suffered both a non-fatal stroke and a non-fatal MI.

Non-fatal MI and non-fatal stroke exclude patients who died (of any cause).

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The effect of clopidogrel did not differ significantly in various prespecified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history. Such subgroup analyses should be interpreted cautiously.

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