Unknowns Predominate in Variable Clopidogrel Response


Even when multiple factors known to affect clopidogrel efficacy are rigorously excluded, there remains substantial variability in both the activation of the drug and its antiplatelet effect, according to a paper published online January 16, 2013, ahead of print in the Journal of the American College of Cardiology. Identifying the unknown sources of this inconsistency may aid in patient management.

Investigators led by Andrew L. Frelinger III, PhD, of Harvard Medical School (Boston, MA), administered 75 mg of clopidogrel daily for 9 days to 160 healthy subjects. None had CYP2C19 polymorphisms affecting clopidogrel metabolism, and all were confined to a clinic on a standard diet, having remained free of nicotine for 6 weeks, prescription drugs for 4 weeks, over-the-counter drugs for 2 weeks, and caffeine and alcohol for 72 hours.

Multivariate analysis controlled for demographic, hematologic, and genetic factors that independently predicted clopidogrel pharmacokinetics. These factors, as well as age and weight, accounted for only about 18% of the observed variation in clopidogrel active metabolite and about 16% of the disparity in peak plasma concentration. That left about 82% of variation with both parameters unexplained.

Wide Range of Pharmacokinetic, Pharmacodynamic Results

At the end of the clopidogrel regimen, exposure to the drug’s active metabolite varied widely. Values for area under the curve (AUC; mean 41.3 ± 14.0 ng/hr/mL) and peak plasma concentration (mean 39.6 ± 15.9 ng/mL) showed more than threefold differences from the 10th to the 90th percentile. Coefficients of variation for the 2 measures were 34% and 40%, respectively.

In the pharmacodynamic analysis, mean platelet function values also varied widely for each of the assays used. Coefficients of variation were:

  • 37% for the vasodilator-stimulated phosphoprotein (VASP; BioCytex, Marseille, France) platelet reactivity index
  • 53% for VerifyNow (VerifyNow, Accumetrics, San Diego, CA) P2Y12 reaction units
  • 37% for maximal platelet aggregation with 5 µM ADP-stimulated light transmission aggregometry (LTA) and 32% for maximal platelet aggregation with 20 µM ADP LTA

Using consensus cutpoints for these assays, 45% of subjects had high on-treatment platelet reactivity by at least 1 criterion.

Patient age and baseline weight were associated with the level of clopidogrel active metabolite (AUC 0.0639; P = 0.0019 and AUC 0.0625; P = 0.0022, respectively), although the 2 factors together accounted for only 5% to 6% of the difference between subjects. Sex, platelet count, and polymorphisms of the CYPC3A5, ABCB1, and PON1genes did not significantly affect clopidogrel pharmacokinetics.

No Genetic Influence

Models for pharmacodynamics, meanwhile, found that VASP-measured platelet reactivity was mainly influenced by clopidogrel active metabolite levels and less so by platelet count and pretreatment reactivity. Genetic polymorphisms had no effect.

Platelet reactivity on the VerifyNow and both LTA assays, on the other hand, was linked not only to clopidogrel active metabolite AUC and peak plasma concentration but also pretreatment VASP platelet reactivity, hematocrit, and sex. For VerifyNow, influential factors included age, clopidogrel active metabolite parameters, hematocrit, and pretreatment VASP and VerifyNow platelet reactivity. Together they explained 65% of the variation in results.

The authors note that the substantial variability in clopidogrel response observed in healthy volunteers would likely be even higher in patients with activated platelets due to ACS or comorbidities such as diabetes.

‘Unknown Unknowns’

In a telephone interview with TCTMD, study coauthor Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), said the distinctive contribution of the study is its demonstration of high variability in clopidogrel response even after subtracting the principal factors known to affect it.

“If you believe that this variability is bad—and you worry about things like genetics or [proton pump inhibitors (PPIs)] or smoking affecting clopidogrel levels—then you need to worry a lot more because there are [multiple] factors that we don’t know about,” he commented.

“[The findings] probably explain why there’s been so much discordance in the field, where some studies show genotype or PPIs, for example, are important and others do not,” Dr. Bhatt continued. “That’s because when you look at any one of these factors in isolation, it’s a drop in the pond. It matters, but it doesn’t matter that much. And there are a lot of other things that we can’t measure that matter at least as much.”

Based on the results of earlier genome-wide association studies, Dr. Bhatt downplayed the chance that important genetic polymorphisms affecting clopidogrel remain to be discovered.

Rationale for Testing Undermined

Meanwhile, the authors question the US Food and Drug Administration ‘black box’ warning that alternative therapies should be considered for CYP2C19 ‘poor metabolizers’ of clopidogrel. In fact, they say, the wide variability in clopidogrel response independent of genetic and other factors “strongly suggests that therapeutic strategies based on [testing for] CYP2C19*2 polymorphism will not eliminate the increased risk for [MACE] in patients with high on-treatment platelet reactivity.”

Interestingly, much of the variability in clopidogrel’s physiological effect appears to arise after its absorption and metabolism, Dr. Bhatt said, adding, “We’re still learning a lot about ADP receptor antagonism” and other, later-stage mechanisms. Factors downstream of the P2Y12 receptor, including glycoprotein IIb/IIIa receptor density, fibrinogen, platelet concentration, and cell-to-cell contact, likely play a role, the authors say.

“There is no point in worrying about this variability until and unless we can characterize all the sources,” Dr. Bhatt said. Pursuing them is a worthwhile research goal, he added, but meanwhile clinicians should not be preoccupied with a few known factors.

“If something isn’t actionable, there’s little point in measuring it,” he concluded.

Study Details

Subjects were aged 18 to 55 years, with BMI between 18 and 30 kg/m. At enrollment, all had normal hematology, clinical chemistry, and urinalysis results. Platelet function was measured at baseline and pre-dose on days 7, 8, and 9 then at 24 hours after the last dose.

 


Source:
Frelinger III AL, Bhatt DL, Lee RD, et al. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors) and pre-existent variability in platelet function. J Am Coll Cardiol. 2013;Epub ahead of print.

 

 

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Unknowns Predominate in Variable Clopidogrel Response

Even when multiple factors known to affect clopidogrel efficacy are rigorously excluded, there remains substantial variability in both the activation of the drug and its antiplatelet effect, according to a paper published online January 16, 2013, ahead of print in the
Disclosures
  • The study was supported in part by a research grant from the Takeda Global Research and Development Center.
  • Dr. Frelinger reports receiving research grants from Eli Lilly and GLSynthesis.
  • Dr. Bhatt reports receiving research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, and The Medicines Company, and performing unfunded research with FlowCo, PLx Pharma, and Takeda.

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