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INTRODUCTION

LEARNING OBJECTIVES

  1. Identify key variants associated with the metabolism and clearance of antiplatelets, beta blockers, statins, and vitamin K antagonists.

  2. Evaluate literature describing the clinical impact of pharmacogenetic variants on safety, efficacy, and patient outcomes when recommending cardiology pharmacotherapy.

  3. Review Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and other relevant guidelines for pharmacogenetics-guided dosing recommendations.

ANTIPLATELET PHARMACOGENOMICS

Clopidogrel and CYP2C19

Antiplatelet therapies are utilized to prevent the glycoprotein IIb/IIIa receptor on platelets from becoming activated by adenosine diphosphate (ADP) binding to the platelet at the P2Y12 portion of the ADP receptor on the platelet surface. In the absence of antiplatelet therapy, activation of the glycoprotein IIb/IIIa receptor enables fibrinogen binding and platelet aggregation. By inhibiting ADP binding to the platelet, P2Y12 inhibitors prevent glycoprotein IIb/IIIa activation and resultant platelet aggregation.1,2 P2Y12 inhibitors, including clopidogrel, prasugrel, and ticagrelor, are used for treatment of acute coronary syndrome (ACS), as well as prevention of recurrent thrombosis following ACS.3,4 Of these options, only clopidogrel and prasugrel must be converted from prodrug to active drug to metabolites to provide optimal therapeutic efficacy, as ticagrelor does not require biotransformation for pharmacologic efficacy.3 Clopidogrel is converted to its active metabolite by CYP1A2, 2B6, 2C19, 2C9, 3A4, and 3A5, with CYP2C19 being the most clinically important.2 Prasugrel is primarily converted to its active metabolite by CYP2B6 and 3A5. CYP2C19, 2C9, 2D6, and 3A4 isoenzymes are also involved in its metabolism to a lesser extent.2

Mechanism of Drug-Gene Interaction

Several pharmacogenomic variants exist that are associated with lower serum concentrations of clopidogrel’s active metabolite, including the CYP2C19*2 allele (rs4244285, c.681G>A), which is the most prevalent no-function allele found in approximately 15% of Caucasians and individuals of African descent and approximately one-third of Asians.5 The serum concentration of clopidogrel’s active metabolite is 30% lower when this variant is present.6 The CYP2C19*3 (rs4986893, c.636 G>A) as well as *4, *5, *6, *7, and *8 alleles occur less commonly, but also have detrimental effects on serum concentrations of clopidogrel’s active metabolite, thus reducing the antiplatelet activity and efficacy of the drug. The mean absolute reduction in platelet aggregation is reported to be significantly lower in both intermediate (–9.1) and poor (–28.7) metabolizers compared to normal metabolizers (p <0.05).7–9 A variant that increases the antiplatelet activity of clopidogrel has also been identified. The CYP2C19*17 (rs12248560, c.806 C>T) allele actually enhances transcription of the gene encoding CYP2C19 and is therefore an increased-function allele, as it enables conversion of a higher percentage of inactive clopidogrel parent drug to active clopidogrel metabolites.8 The presence of CYP2C19 variants has not been shown to decrease serum concentrations or efficacy of prasugrel.10 Since ticagrelor does not require conversion to an active metabolite and CYP2C19 variants do not affect prasugrel efficacy, currently the only antiplatelet with efficacy ...

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