Evidence map›Paper›PMID 26524713›Full record

Trial reportEuropean journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences2016

Development of a physiology-directed population pharmacokinetic and pharmacodynamic model for characterizing the impact of genetic and demographic factors on clopidogrel response in healthy adults.

Xi-Ling Jiang, Snehal Samant, Joshua P Lewis, Richard B Horenstein, Alan R Shuldiner, Laura M Yerges-Armstrong, Lambertus A Peletier, Lawrence J Lesko, Stephan Schmidt

Registry-linked trialOpen access · greenAbstract readClinical Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01341600 (Clopidogrel Pharmacogenetics Bench to Bedside - A Practical Application), which is not on this map. Cited by 20 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
20citing papers in PubMed, 1 pooled it
1.1field-weighted citation impact, top 20% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01341600 nacompletednot on this map

Clopidogrel Pharmacogenetics Bench to Bedside - A Practical Application

TypeinterventionalSponsorUniversity of Maryland, BaltimoreRan2010 to 2011Enrolled18ConditionsMetabolism of ClopidogrelArmsClopidogrel, Omeprazole/Clopidogrel
3 · Its place in the literature

Who cites it

20 citing papers in PubMed, 1 synthesis or guideline pooled it, 32 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. Article
  4. Regulation of Human Hydrolases and Its Implications in Pharmacokinetics and Pharmacodynamics.Drug metabolism and disposition: the biological fate of chemicals · 2024
    Review
  5. Article
  6. Article
  7. Article
  8. Review
  9. Review
  10. Article
  11. Pharmacogenomics Informs Cardiovascular Pharmacotherapy.Methods in molecular biology (Clifton, N.J.) · 2022
    Article
  12. Article
  13. Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators.Drug metabolism and disposition: the biological fate of chemicals · 2020
    Review
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors at 3 institutions in 2 countries.

Xi-Ling JiangDepartment of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, FL, USA.
Snehal SamantDepartment of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, FL, USA.
Joshua P LewisDivision of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
Richard B HorensteinDivision of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
Alan R ShuldinerDivision of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
Laura M Yerges-ArmstrongDivision of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
Lambertus A PeletierMathematical Institute, Leiden University, PB 9512, 2300 RA Leiden, The Netherlands.
Lawrence J LeskoDepartment of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, FL, USA.
Stephan SchmidtDepartment of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, University of Florida at Lake Nona, Orlando, FL, USA. Electronic address: sschmidt@cop.ufl.edu.
University of Florida · USUniversity of Maryland, Baltimore · USLeiden University · NL

Funding

Pharmacogenomics of CVD risk ReductionU01GM074518 · UNIVERSITY OF MARYLAND BALTIMORE · 2005 to 2005
$1.3M
NCATS NIH HHS UL1 TR000064NCATS NIH HHS UL1TR000064NIGMS NIH HHS GM074518-05NIGMS NIH HHS GM074518-05S1NIGMS NIH HHS U01 GM074518
6 · The paper itself

Abstract

Clopidogrel (Plavix®), is a widely used antiplatelet agent, which shows high inter-individual variability in treatment response in patients following the standard dosing regimen. In this study, a physiology-directed population pharmacokinetic/pharmacodynamic (PK/PD) model was developed based on clopidogrel and clopidogrel active metabolite (clop-AM) data from the PAPI and the PGXB2B studies using a step-wise approach in NONMEM (version 7.2). The developed model characterized the in vivo disposition of clopidogrel, its bioactivation into clop-AM in the liver and subsequent platelet aggregation inhibition in the systemic circulation reasonably well. It further allowed the identification of covariates that significantly impact clopidogrel's dose-concentration-response relationship. In particular, CYP2C19 intermediate and poor metabolizers converted 26.2% and 39.5% less clopidogrel to clop-AM, respectively, compared to extensive metabolizers. In addition, CES1 G143E mutation carriers have a reduced CES1 activity (82.9%) compared to wild-type subjects, which results in a significant increase in clop-AM formation. An increase in BMI was found to significantly decrease clopidogrel's bioactivation, whereas increased age was associated with increased platelet reactivity. Our PK/PD model analysis suggests that, in order to optimize clopidogrel dosing on a patient-by-patient basis, all of these factors have to be considered simultaneously, e.g. by using quantitative clinical pharmacology tools.

Indexed as

Models, BiologicalAdultClopidogrelDemographyFemaleGenotypeHumansLiverMaleMiddle AgedPlatelet AggregationPlatelet Aggregation InhibitorsTiclopidineClopidogrelPlatelet Aggregation InhibitorsTiclopidineCES1ClopidogrelCYP2C19PharmacogeneticsPhysiology-directed population pharmacokinetic and pharmacodynamic modelPK/PD modeling

Identifiers

PMID26524713
PMCPMC5798599
OpenAlexW2219320457

What Socratic holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.