**7. Conclusion**

198 Pharmacology

The guidelines for European Medicines Agency (EMEA) was desighned by the Agency's committee for Human Medicinal Products (CHMP). The rationale for this guidelines include standardization, data analysis, interpretation, evaluation of clinical relevance, ethical consideration and setting the stage for technical, scientific and regulatory issues. The

ii. the population selected for pharmacogenetic studies (i.e. species, age, gender and other

iii. The population size selected for PG studies and a discussion on the power to detect an

iv. Predictive values (positive and negative) of the PG biomarkers as per clinical trials

v. Assumptions on clinical utility e.g. benefit In using predictive pharmacogenetics testing versus other predictive biomarkers, use of a pharmacogenetic biomarker as a segregation marker or as a stratification tool for a subpopulation in a general matching population.

The overall purpose of PG testing is clinical benefits. Pharmacogenetic testing have resulted in some clinical benefit so far, some of which can be life saving. It was observed that roughly about 106,000 deaths and 2.2 million serious events caused by adverse drug reactions were reported yearly (Lazarom 1998) and 5 – 7% of hospital admissions in US and Europe lead to the withdrawal of 4% of new medicines with attendant financial loss. Since such drugs were linked to metabolizing enzymes with known polymorphism,prudence dictates suggestion of pharmacogenetic testing in indicated instances Pharmacogenetics testing is expectedly becoming commonly required particularly with drugs with low therapeutic window (Phillips et al 2001). However, the decision to use pharmacogenetic testing will be influenced by the relative costs of genotyping technologies and the cost of providing a

Notable clinical benefits of pharmacogenetic testing have been observed in NAT2 genotyping for isoniazid treatment (Hiratsuka et al 2002, Weishilboum et al 2003, Gardiner and Begg 2006) andCYP2C19 genotyping for omeprazole treatment (Desta et al 2002).

Others are TPMT genotyping for 6-mercaptopurine and azathioprine treatment (Relling et al 1999, Gardener and Begg 2006) mtDNA A155G genotyping for aminoglycoside treatment (Cortopassi and Hatchin 1994, Usami et al 1999) CYP 2D6 genotyping for codeine treatment (Bradford 2002) Hepatitis C genotype for pegylated interferon – alpha – 2a or pegylated – interferon – alpha – 2b treatment. (Ingelman – Sundberg et al 2009, Thomas et al 2009) and Dihydropyrimidine dehydrogenese (DPI) testing for 5-fluoro-Uracil (5FU) treatment (Gionzalez and Fernandez –Salguero, 1995, McMurrough et al 1996, Wei et al 1996, Van

\*In the study population e.g. matched groups (responders/non responders,

variable related to the phenotype e.g. for human exposure ethnic group)

**6.1 European medicines agency guideline for pharmacogenetic testing** 

guidelines addresses the following among other issues.

\*In the target population or relevant animal model

presence/absence of adverse events)

**6.2 Pharmacogenetic testing and clinical benefits** 

treatment to a patient with an incompatible genotype.

i. Chosen design and rationale

association in appropriate

experience

Kuilenburg et al 1998).

With the application of molecular biology methods and completion of the human genome projects and establishment of guidelines for pharmacogenetics practices and applications, it is expected that the interwoven field of pharnmacogenetics and pharmacogenomics will revoluntionise personalized medicine. Furthermore the field of predictive medicine is expected to receive a boost from pharmacogenetic information with attendant reduction in morbidity and mortality particularly from adverse drug reactions and therapeutic failure. With more intense researches and genotyping profiling, the challenges of standardization and interpretation of pharmacogenetic testing are apt to be overcome. It is worthy of note that currently some drug labels carry information on pharmacogenetic testing and requirements for therapeutic use. The promise of pharmacogenetics is therefore improvement of the overall health being of the patients.

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**1. Introduction** 

**1.1 Complexity of pharmacogenetics of CVDs** 

**1.2 The aim of this book chapter** 

William K. Redekop3 and Rahber Thariani4 # These authors contributed equally *1Utrecht University, The Netherlands* 

*4University of Washington, USA*

*2Leiden University Medical Center, The Netherlands 3Erasmus University Rotterdam, The Netherlands* 

 \*

**10** 

*Utrecht University The Netherlands* 

**Future of Pharmacogenetics in** 

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.

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

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

be taken into account if a pharmacogenetics based dosing strategy is developed.

that could improve research of pharmacogenetic interactions in CVD.

Anthonius de Boer1, Tom Schalekamp1, Felix J.M. Van Der Meer2,

**Cardiovascular Diseases** 

Rianne M.F. Van Schie#, Talitha I. Verhoef# and Anke-Hilse Maitland-Van Der Zee et al.\*

