Pharmacogenomics and Anti-platelet/ Anticoagulant Therapy- Aquah mensa

Why is platelet aggregation a target in the management of Coronary Artery Disease (CAD)?

Platelet adhesion and aggregation are early stages in the formation of a thrombus leading to occlusion of the coronary artery

What is the role of the P2Y12 receptor in platelet aggregation?

P2Y12 receptor is coupled to Gi-protein in the platelet membrane, activated by ADP (release from activated platelets) and inhibits adenylyl cyclase, inducing platelet aggregation

What factors account for the highly variable response to clopidogrel

Variations in absorption, transport, metabolism, target/receptor

What percentage of patients do not obtain optimum benefit of clopidogrel?

20-40%

How is clopidogrel metabolized?

conversion to carboxylic acid by an esterase (CES1), forming an inactive metabolite. Step 1 of active metabolism requires CYP2C19, 1A2, 2B6 enzymes for oxidation to 2-oxo-clopidogrel. Step 2 of active metabolism requires CYP2C9, CYP2C19, 2B6, 3A4, and 3A5 to form an active metabolite.

What ABCB1 polymorphism impacts the bioavailability of clopidogrel?

P-gp 3435 TT genotype has lower bioavailability than CC genotype with loading doses of 300-600 mg. At 900 mg, the bioavailability in Pts with 3435 TT genotype is much greater compared to 3435 CC. MDR12 homozygotes have lower bioavailability than MDR11 following loading doses of 300-600 mg

What polymorphism of CES1 results in better outcomes with clopidogrel?

G143E mutation gives rise to higher levels of active metabolite than those homozygous for 143G

When are loss-of-function CYP3A5 alleles relevant to the processing of clopidogrel?

When clopidogrel concentrations are above 10 mcg, it auto-inhibits its own activation via CYP2C19 and CYP3A5 takes over to activate it. If the function of CYP3A5 is lost, then the amount of active metabolite is lower and the Pt is at risk of thrombosis

For clopidogrel therapy, which paraoxonase 1 (PONI) polymorphism is associated with poor outcomes?

Q192R variant

What do many hospitals use as standard of care DAPT?

Aspirin + clopidogrel

What advantages, if any, does clopidogrel have over third generation anti-platelet drugs?

Lower bleeding risk, less expensive

What are the FDA/CPIC/DPWG recommendations for CYP2C19 intermediate metabolizers?

The FDA doesn't have any recommendations, CPIC recommends choosing another anti-platelet agent, DPWG recommends choosing another anti-platelet agent or doubling the dose to 150 mg/day

What are the FDA/CPIC/DPWG recommendations for CYP2C19 poor metabolizers?

FDA/CPIC/DPWG recommend choosing an alternative anti-platelet agent such as prasugrel or ticagrelor

What do prasugrel and clopidogrel have in common?

They're both pro-drugs that irreversibly inhibit P2Y12 receptors as an antagonist

How does prasugrel differ from clopidogrel?

-Unlike clopidogrel, most of prasugrel is converted to the active metabolite-Prasugrel is primarily activated by CYP3A5 and CYP2B6, and to a lesser extent by CYP2C19-Genetic variations in CYP3A5/2B6 do not have relevant effect on prasugrel's kinetics

What do prasugrel and ticagrelor have in common?

They're both third generation anti-platelet drugs

How does ticagrelor differ from prasugrel?

-Ticagrelor is not a prodrug, but it does have an active metabolite-Ticagrelor reversibly inhibits P2Y12 receptors

Which polymorphism of PTSG1 impacts resistance to aspirin therapy?

PTGS1 rs10306114: individuals with the AA genotype treated with aspirin may have a decreased risk for non-response to aspirin compared to those with the AG or GG genotype

What HLA allele is associated with increased risk of asthma with aspirin treatment?

HLA-DPB1*03:01:01 allele

What is the mechanism of action of warfarin?

Competitively inhibits VKORC1, which is an essential enzyme for activating vitamin K

What vitamin activates blood clotting factors?

Vitamin K

What is the goal for warfarin treatment?

To achieve an INR in a target range for the condition being treated, most commonly 2-3

What are the principal gene variants that impact outcomes in warfarin treatment?

VKORCI mutations require a decreased dose of warfarin compared to wild type; reduction in dose is larger for homozygous genotype AA and TT

What are some examples of drug-drug interactions that can impact warfarin treatment outcomes?

amiodarone, fluconazole, metronidazole, NSAIDs, broad spectrum antibiotics

What are some examples of food-drug interactions that can impact warfarin treatment outcomes?

Green leafy vegetables, liver, broccoli, brussels sprouts

Which ethnic group often requires higher warfarin doses?

Africans

What genetic variants are unique to the African population in terms of warfarin treatment?

-CYP2C gene cluster, rs12777823-CYP2C9 5, 6, 8, 11

How does the CYP4F2*3 variant impact warfarin dosing?

It's associated with modest increases in warfarin dose requirements in Europeans and Asians

How do variants of a CYP2C cluster impact dosing in Africans?

rs12777823 AG and AA genotypes are associated with decreased warfarin dose requirements

What polymorphism reduces the risk of dabigatran-induced bleeding?

CES1 rs2244613