**1. Introduction**

206 Pharmacology

Wool house WM, Qureshi MM, Bastaki SMA, Patel M, Abchilrazzaq, Y, Bayoumi RAL

Yamaka Y, Hamada A, Nakashima R, Yuki M, Hirayama C, Kawaguchi T and Saito H (2011)

Zhou Q, Kibat C, Cheung YB, Tan EH, Ang P, Balran C (2004) Pharmacogenetics of

myeloid leukaemia *.Therapeutic Drug Monitoring 33(2):244-250* .

*Pharmacogenetics 7:73 – 82* 

*meeting Edition) 22 (145) : 3014*

(1997). Polymorphic N – acetyltranseferase (NAT2) genotyping of Emiratis

Association of genetic polynmorphism in the influx transporter SLCOIB3 and the efflux transporter ABCB1 with Imatinib pharmacokinetics in patients with chronic

epidermal growth factor receptor (EGFR) gene in Chinese, Malay and Indian populations.*Journal of Clinical Oncology: ASCO Annual Meeting Proceedings (Post* 

> Pharmacogenetics is the study of variations in DNA sequence as related to drug response (European Medicines Agency [EMA], 2007). Several gene-drug interactions have been discovered in the field of cardiovascular diseases (CVDs). These gene-drug interactions can help to identify nonresponse to drugs, estimate dose requirements or identify an increased risk of developing adverse drug reactions. An individualized approach based on pharmacogenetic testing will provide physicians and pharmacists with tools for decision making about pharmacotherapy. While pharmacogenetic testing is already part of everyday practice in oncology, it is not widely implemented in the field of CVDs. However, in the near future, pharmacogenetics will probably also play a valuable role in this field as well.

#### **1.1 Complexity of pharmacogenetics of CVDs**

Prophylaxis and treatment of CVD is complex. Patients often have more than one cardiovascular risk factor (e.g. hypertension and hypercholesterolemia) and/or CVD, or other comorbidities such as diabetes mellitus. Frequently, more than one drug is used by the patient and this may potentially lead to serious drug interactions with adverse health outcomes. Therefore, not only the comorbidities but also the interaction between co-medications should be taken into account if a pharmacogenetics based dosing strategy is developed.

#### **1.2 The aim of this book chapter**

The aim of this book chapter is to describe and explore several examples of gene-drug interactions in CVD, the factors that affect the implementation in clinical practice, the costeffectiveness analysis of pharmacogenetic testing, and the development of new technologies that could improve research of pharmacogenetic interactions in CVD.

<sup>\*</sup> Anthonius de Boer1, Tom Schalekamp1, Felix J.M. Van Der Meer2,

William K. Redekop3 and Rahber Thariani4

<sup>#</sup> These authors contributed equally

*<sup>1</sup>Utrecht University, The Netherlands* 

*<sup>2</sup>Leiden University Medical Center, The Netherlands* 

*<sup>3</sup>Erasmus University Rotterdam, The Netherlands* 

*<sup>4</sup>University of Washington, USA*

Future of Pharmacogenetics in Cardiovascular Diseases 209

thrombosis, myocardial infarction, stroke and cardiovascular death. Clopidogrel monotherapy may be used for secondary prevention of atherosclerotic complications, in

Clopidogrel is administered to patients as a prodrug. It needs to be metabolized by several hepatic cytochrome P450 (CYP) enzymes in order to form the active platelet aggregation inhibiting metabolite. This is done in two steps. During the first step, the intermediate 2-oxoclopidogrel metabolite is formed. In this step three isoenzymes (CYP1A2, CYP2B6 and CYP2C19) are involved. During the second step this metabolite is hydrolyzed into the active thiol derivative R-130964, which blocks the ADP P2Y12 receptors on the platelet surface, causing inhibition of platelet aggregation. This step is catalyzed by four isoenzymes

Although the effectiveness of clopidogrel has been demonstrated in many trials, variation in response is still an issue. Some patients experience cardiovascular events despite dual antiplatelet therapy (Yukhanyan et al., 2011). This difference in risk of cardiovascular events is genetically determined. In addition, response-variability is also caused by a genetically determined difference in platelet aggregation (Harmsze et al., 2010a). The interindividual variability in response to clopidogrel can be explained by multiple genetic and environmental factors. Variation in response to clopidogrel related to genetic variability in the *CYP2C19* gene has been investigated thoroughly, as the CYP2C19 enzyme plays an important role in both metabolizing steps (Anderson et al., 2010). In several studies a relationship between carriage of a loss-of-function allele in the *CYP2C19* gene and the occurrence of adverse cardiovascular events has been demonstrated. Up to now, more than 33 alleles of the *CYP2C19* gene have been identified. Most of these are rare in the general population. The most common allele in the European population is *CYP2C19*\*1. The enzyme encoded by this allele enables extensive metabolizing of clopidogrel into the active metabolite. A common variant allele is the \*2 allele. Patients carrying at least one of this variant allele have a decreased activity of the CYP2C19 enzyme. This leads to a reduced plasma concentration of the active metabolite and possibly to an increased risk of recurrent cardiovascular events. Knowledge of the *CYP2C19*\*2 genotype can explain approximately 12% of the variation in response to clopidogrel. An increased risk of stent thrombosis has been demonstrated in carriers of a *CYP2C19*\*3 allele. Both carriers of a \*2 of a \*3 allele have a decreased enzyme activity, resulting in a lower amount of active metabolite (Harmsze et al., 2010b). The *CYP2C19*\*17 allele however, encodes for a more active enzyme. Carriers of this allele therefore have an increased antiplatelet response to clopidogrel. This might be associated with an increased risk of bleeding (Yukhanyan et al., 2011; Zabalza et al., 2011). Pharmacogenetic testing for the \*2 or \*3 variant alleles could identify patients that are less likely to respond to clopidogrel and who might benefit more from treatment with an alternative, more expensive PI such as prasugrel or ticagrelor. Prasugrel and ticagrelor have less variability in response than clopidogrel, mainly due to a smaller influence of genetic variations. However, patients using prasugrel or ticagrelor have an increased risk of bleeding compared to patients using clopidogrel (Jakubowski et al., 2011; Collet & O'Connor, 2011). At the moment, randomized controlled trials (RCTs) are ongoing to evaluate the (cost) effectiveness of pre-treatment genotyping (Crespin et al., 2011). Based on the results of these trials, physicians can decide whether or not to prescribe clopidogrel or

case aspirin can not be used, for example due to allergy (Anderson et al., 2010).

(CYP2B6, CYP2C9, CYP2C19 and CYP3A4) (Yukhanyan et al., 2011).

another PI on the patient's genotype.
