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YOUNG INVESTIGATORS
Asian Study of Thienpyridine Drug Interactions (ASThien-DI)

Platelets have an important role to play in the clotting of blood. When platelet aggregation is not under control, excessive aggregation occurs, leading to the blockage of the blood vessels. Reduction in blood supply or the dislodging of clots from their site of origin may damage vital organs like the brain or heart; leading to a stroke or heart attack. [1], [2]

Thienopyridine drugs such as Ticlopidine, Clopidogrel and Prasugrel are anti-platelet drugs commonly prescribed for patients to prevent excessive platelet aggregation. Ticlopidine, approved by FDA in 1991, is currently rarely used because of the risk of serious side effects including aplastic anemia. Clopidogrel was approved in 1997 while Prasugrel was approved only in 2009. [3] Studies have shown that Prasugrel in a 60 mg loading dose was found to inhibit adenosine diphosphate (ADP)-induced platelet aggregation more rapidly, consistently and to a greater extent than a 300 mg standard loading dose of Clopidogrel in both healthy volunteers and patients undergoing Percutaneous Coronary Intervention (PCI). [4] Compared to standard doses of Clopidogrel, Prasugrel is more efficiently metabolized to its active metabolites, providing a more pronounced platelet inhibition with less inter-subject variability. [2] Despite these, Prasugrel is still less frequently prescribed compared to Clopidogrel. This could possibly be due to the fact that Clopidogrel is comparatively more affordable and has been in the market for a longer duration compared to Prasugrel.

Studies have also shown that there was significant inter-individual variability in patients’ responses to Clopidogrel. Clopidogrel is a pro-drug that has to undergo a complex biochemical pathway before it is converted into an active form which binds specifically and irreversibly to the platelet P2RY12 receptor, inhibiting ADP-mediated platelet activation and aggregation. There are various genes modulating the intestinal absorption (ABCB1) and the metabolic activation of Clopidogrel in the liver by cytochrome P450 isoenzymes (e.g. CYP2C19, 3A5) as well as Paraoxonase PON-1. The activity of CYP 450 isoenzymes are affected by environmental influences, drug-drug interactions and single nucleotide polymorphisms. [7] These may in turn result in variations in the amount of active metabolite produced.

Smoking is one environmental factor that has been shown to enhance the inhibition of platelet aggregation directly as well as via the induction of CYP 1A2 activity that is involved in the metabolic activation of Clopidogrel. [8] This leads to the patient’s hyper-responsiveness to Clopidogrel, and so increases the risk of bleeding.

Patients who are on Clopidogrel are commonly on many other medications (polypharmacy) due to the complexity of their medical conditions. Research has shown that drugs from classes such as proton pump inhibitors, lipophilic statins and dihydropyridine calcium channel blockers reduce the effect of Clopidogrel by competing for CYP, and/or inhibit CYP 2C9, CYP 2C19 and CYP 3A4 isoenzymes that are required for Clopdigorel to take effect. [7], [9], [10] Hence, the concurrent use of any of such drugs may result in patients having a poor response to Clopidogrel and the inability to prevent the formation of blood clots as effectively. Table 1 below shows examples of commonly used drugs that interact with Clopidogrel.

Single nucleotide polymorphisms (SNPs) are single DNA nucleotides whereby one base is substituted by another. The base replacement can lead to a change in the amino acid sequence which in turn affects the protein produced. This may or may not affect the enzymatic activity. [11] Single nucleotide polymorphisms of CYP 2C19*2/ *3/ *17, ABCB 1, CYP3A5*3 and CYP 2B6 have been found to contribute to inter-individual responses towards Clopidogrel response. [10]

Paraoxonase-1 (PON 1) is the most recent implicated SNP which demonstrated that patients with a mutated PON 1 gene have a higher risk of stent thrombosis. [12] Among the SNPs, ABCB 1, CYP 2C19*2/ *3 and CYP 3A5*3 have been found to result in loss-of-function or decreased activity of cytochrome, leading to a decrease in activation of Clopidogrel. On the other hand, CYP 2C19*17 and PON 1 have been found to increase the activity of cytochrome leading to an increase in activation of Clopidogrel.

Genetic variations and drug interactions may attenuate the antiplatelet effect of Clopidogrel. Hypo-responsiveness to Clopidogrel (and thus suboptimal inhibition of platelet aggregation) has been linked to a heightened risk of adverse ischemic events or thrombotic complications post-PCI.

The preliminary findings of the Asian Study of Clopidogrel Pharmacogenetics (ASCLOP) based on 53 Asian subjects revealed that CYP 2C19*2 and 3A5*3 variations were the most prevalent, with the latter likely to be more significant in Singapore’s local population. It was also observed that, in patients who were CYP 3A5*3 poor responder variants, having concomitant 3A4-inhibiting drugs dampened Clopidogrel’s antiplatelet effect.

This ASThien-DI study is a joint research project between Khoo Teck Puat Hospital and Republic Polytechnic. A total of 63 patients who were on Clopidogrel during the study period were recruited and had their blood drawn (2X3ml EDTA tubes) for genotyping and (1X1.8ml Sodium Citrate 3.2% tube) for measuring platelet reactivity using the VerifyNow meter. The blood samples were sent to the National University of Singapore for analysis in which genotyping was using the polymerase-chain reaction-restriction fragment length polymorphism (RFLP) assay. Platelet reactivity was measured using the VerifyNow meter, which is an easy-to-operate point-of-care device. It is a turbidimetric-based optical detection system which measures platelet-induced aggregation as an increase in light transmittance. It is an FDA-labelled whole blood assay used to measure the level of platelet P2Y12 receptor blockade. A Platelet Reactivity Unit (PRU) of >235 shows high platelet reactivity or poor response to Clopidogrel.

Results from the study showed that environmental factors and the concurrent use of interacting drugs do indeed lead to inter-individual variability in patients’ response to Clopidogrel. Other possible factors may include gender and ethnicity. Based on this study, females were shown to have higher ratio of non-responders as compared to males. A comparison between Chinese, Malays and Indians in the sample population revealed that Indians have a higher ratio of non-responders as compared to the other ethnic groups. Although many studies have shown that concurrent use of interacting drugs affect Clopidogrel response, [13], [14] data analysis via the use of Chi Square and Fisher’s Test in this study show that there is no statistically significant difference between the wild type and mutant gene of CYP 3A5*3 with regards to the response of Clopidogrel on patients who took lipophilic statins and dihydropyridines; and CYP 2C19*2/ *3/ *17 for those who took proton pump inhibitors concurrently with Clopidogrel.

In conclusion, the type of genes (wild type versus mutant) may not be the sole causative factor leading to variations in Clopidogrel response. Other factors such as levels of enzyme expression, environmental influence and even patient-specific parameters like diet or lifestyle may play a role as well.

About the NFIA

Geraldine Lai Dunlin a graduate from the Republic Polytechnic School of Applied Science, Diploma in Pharmaceutical Science. Academically, she was inducted into the Roll of Honours List in AY2012 Semester 1 and the winner of Module award for Patient Care in AY2012 Semester 2. She embarked on a one-year-long final year project (FYP) in collaboration with Khoo Teck Puat Hospital. Her FYP (Asian Study of Thienopyridine-Drug Interactions (ASThien-Di) was selected to represent Republic Polytechnic in the Young Scientist Symposium held on 13th March 2013 at the Singapore Science Centre. The project's findings also qualified as one of the top 100 poster exhibits at the BioPharma Asia Convention 2013 held from 18-21 March 2013.

Ong Sher Lyn graduated with a Diploma in Pharmaceutical Sciences (Merit) from Republic Polytechnic. This team-based Final Year Project titled, 'Asian Study of Thienopyridine-Drug Interactions (ASThien-Di)' is her first stepping stone into the field of R&D for biotech-pharma related industries. Continuing her quest to broaden her understanding as well as exploring newer pastures, Sher Lyn is currently awaiting commencement into Nanyang Technological University to read a double degree in Biological Science and Psychology.

 

See Jing Rou, is a graduate from Republic Polytechnic, School of Applied Sciences. She is the recipient of the Gold Medal Award in Diploma in Pharmaceutical Sciences. During her study in Republic Polytechnic, she has won several module prizes and was consistently on the academic roll of honours. She took up a one-year-long Final Year Project in collaboration with Khoo Teck Puat Hospital (KTPH), Singapore entitled Asian Study of Thienopyridine-Drug Interactions (ASThien-Di). This project was selected to represent Republic Polytechnic to present the project's finding at the Young Scientist Symposium 2013. The project findings were also qualified as one of the top 100 posters exhibited at the BioPharma Asia Convention 2013.

Lily Yani is an Indonesian who pursued her study in Singapore after graduating from senior high school in Indonesia. She graduated with a Diploma in Pharmaceutical Sciences with Merit from Republic Polytechnic. Her Final Year Project was a study to determine Thienopyridine-Drug interactions amongst an Asian population. This project was selected to represent Republic Polytechnic to present the project's findings at the Young Scientist Symposium 2013. The project findings were also qualified as one of the top 100 posters exhibited at the BioPharma Asia Convention 2013. She is looking forward to pursue her interest in laboratory work.

Lim Jia Min comes from Johor, Malaysia. When she was 18 years old, she left Malaysia to pursue a Diploma in Pharmaceutical Sciences at Republic Polytechnic, Singapore where she graduated with Merit in 2013. While in Republic Polytechnic, she was on the academic roll of honours and received the merit award for 2010 and 2011. Her Final Year Project was an Asian Study of Thienopyridine-Drug Interactions (ASThien-Di) which was presented at local conferences in Singapore. She will begin her undergraduate studies, reading for a Bachelor of Science (Chemistry) at National University of Singapore, in August 2013.

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