Author + information
- Arwa M. Amin Mostafa1,
- Lim Sheau Chin1,
- Dzul Azri Mohamed Noor1,
- Hamza Mohamed Amin Mostafa1,
- Muhamad Ali SK Abdul Kader2,
- Yuen Kah Hay1 and
- Baharudin Ibrahim1
Clopidogrel is crucial for dual antiplatelet therapy. However, clopidogrel attenuated response may cause therapeutic failure. Although CYP2C19 *2 and *3 alleles are associated with clopidogrel attenuated response, CYP2C19 genotyping is not sufficient to predict the response. Nuclear magnetic resonance spectroscopy (NMR) pharmacometabonomics analysis has been used to predict drug response. An integration of pharmacometabonomics and CYP2C19 genotyping may provide good prediction of clopidogrel response. We aimed to evaluate the integration of pharmacometabonomics analysis of plasma and CYP2C19 genotyping for predicting clopidogrel response.
71 coronary artery disease (CAD) patients who were planned for elective interventional angiographic procedure (IAP) were genotyped for CYP2C19 *2 and *3 alleles. NMR pharmacometabonomics analysis of patients' plasma samples pre-dose and 6 hours post clopidogrel 600mg (Plavix®) loading dose (LD) was applied. Platelets function testing (PFT) was done using the VerifyNow P2Y12 assay. Two cut-off points were used to indicate response; P2Y12 reaction unit (PRU) value > 208 and percentage of inhibition (%Inh) < 15%. Multivariate logistic regression (MVLR) was used to identify the best discriminating metabotype. Integrative pharmacometabonomics-pharmacogenetics models were developed. The Area under receiver operating characteristic (AUROC) was used to evaluate models.
From 71 patients, 41 (57.75%) were carriers of at least one allele of CYP2C19*2 allele while 5 (7.0%) were carriers of CYP2C19*3 allele. Mean PRU of CYP2C19*2 homozygous mutation (*2/*2) (232.73, SD: 33.100) was significantly higher than wild type (*1/*1) (178.17, 68.224) and heterozygous (*1/*2) (181.20, SD: 56.246). However, mean PRU of wild type and heterozygous were not significantly different. Similar significance differences were observed in median %Inh. Overall accuracies and AUROC of pharmacometabonomics models and integrative models are detailed below.
|Model||Pharmacometabonomics Model||Pharmacometabonomics- Pharmacogenetics Integrative Model|
|Pre-dose PRU > 208||68.6||0.644||72.9%||0.727|
|Pre-dose %Inh < 15||63.4%||0.729||70.4%||0.801|
|Post-dose PRU > 208||76.5%||0.734||77.9%||0.762|
|Post-dose %Inh < 15||71.0%||0.789||79.7%||0.846|
Using integrative pharmacometabonomics-pharmacogenetics approach improved clopidogrel response prediction and it can be a preeminent approach to tailor antiplatelet therapy.