Concept and putative application of pharmacogenetics and pharmacogenomics.

• Author: Shah, Jai

Abstract

Pharmacogenetics and pharmacogenomics, the study of how genotype affects drug response, represent a promising paradigm that aims to improve drug development, reduce adverse reactions, and maximize efficacy in drug dosage and prescription. This paper provides a foundation for understanding the scientific basis and putative application of pharmacogenomics for drug discovery, development, licensing and delivery to patients by discussing relevant terminology, types of genetic variation, and providing examples which highlight its multifaceted nature and complex mix of actors and interactions. From basic research to clinical trials, regulatory processes, marketing and prescription to patients, pharmacogenomics will interface with the regulatory and healthcare environment in a multitude of ways and will meet with resistance at various points. Its emergence will also demand the consideration of a number of ethical, legal and social implications, and may require the use of legislative and policy tools to ensure that the benefits of this technology are made available fairly and equitably.

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Introduction

The accumulation of genetic data, punctuated by the publication of the draft sequence of the human genome in February 2001, has provided the scientific community with information that should enable a better understanding of biological mechanisms and disease development in coming years and decades. To date, however, genetics-based treatments are few and far between despite widespread anticipation and media coverage, although there are claims that this is about to change.

One example of this is that mechanisms responsible for the wide variation in patient response to drugs, ranging from optimal efficacy to non-response to adverse reactions (ADRs (1)), are thus far largely unresolved. In the 1950s, Arno Motulsky first conceptualized and investigated the effect of inheritance on individual drug response, leading to a large and growing body of work now known as pharmacogenetics and only recently beginning to reach critical mass. (2) Through the linkage of specific gene, transcript or protein variants with specific response to medicines, pharmacogenetics (and its subsequent broadening, reflected in the term pharmacogenomics) aims to make drug discovery, development and delivery more rational. It is ultimately hoped that ADRs will be minimized and treatment efficacy increased, thereby improving health and health care in both human and monetary terms.

The safety and efficacy arguments for pharmacogenomics hold opportunities as well as challenges for various actors. For pharmaceutical companies, pharmacogenomics could increase the number of drug targets discovered, allow better discrimination between promising candidates and those with less potential, and improve the success rates of clinical trials. Regulators argue that elucidating robust correlations between genotype and drug response will speed up approval for effective candidates while reducing withdrawals that occur after a drug has entered the marketplace. Healthcare providers and insurers believe that pharmacogenomics will raise patient compliance and completion rates and reduce trial-and-error in prescribing. Health systems planners and decision-makers appreciate the potential monetary savings gained from avoiding ADRs, but must decide how to implement policies to harness the technology's benefits while minimizing its intrinsic threats and challenges.

Thus, the scientific foundation and putative application of pharmacogenomics remain difficult concepts to grasp. The complexity of the field necessitates clarity about what pharmacogenomics aims to do; complexity also means that its outcomes are likely to have multiple dimensions requiring consideration. This paper aims to serve as an introduction to pharmacogenetics and pharmacogenomics by exploring relevant terminology and the measurement of genetic variation, providing examples which highlight different aspects of the field, and discussing the role of genotype-phenotype correlation as applied to drug development. Far from being a clear-cut application of a scientific idea, pharmacogenomics is a multifaceted concept that is predicted to have effects at each of the discovery, development and delivery stages. In turn, the emergence and evolution of the discipline will raise a number of ethical, legal, social and policy issues that are now being investigated.

Terminology and Concepts

Pharmacogenetics and pharmacogenomics

It is first useful to define important terms given the technical nature of the topic. Pharmacogenetics, which became widely acknowledged in the 1990s, is based on the concept that inherited DNA, RNA, and protein-level differences influence metabolism and thereby individual patients' response to drugs. Those studying pharmacogenetics test the hypothesis in vitro and in vivo that the reason why certain patients respond well to a particular drug or dosage, while others do not, has a genetic basis.

Pharmacogenomics is a broader concept that examines the differential effects of various drugs across the genome or on the expression of multiple genes, largely in vitro (including DNA, RNA and proteins), and endeavours to develop new compounds to target these molecules. (3) Although conscious attempts to harmonize the various definitions of pharmacogenetics and pharmacogenomics have recently been made, including by the European Agency for the Evaluation of Medicinal Products (4), in practice both terms are used loosely and interchangeably in the literature, as they are here.

The subtle distinction between pharmacogenetics and pharmacogenomics has relevance even though both link together genotype with drug response. Since pharmacogenetics is primarily concerned with patient reaction to a particular medicine (i.e. considers patient variability), it may be clinically useful to identify the most appropriate medicine for an individual suffering from a particular disorder (given his/her genetic background)--"one drug across many genomes". As part of the broader study of how patterns of gene expression respond to various drugs (i.e. compound variability), however, pharmacogenomics incorporates pharmacogenetic approaches but is also relevant to earlier stages of drug development, such as when considering which of a series of compounds to evaluate further--"many drugs across one genome". As a result, while pharmacogenetics could be applied immediately to existing drugs and development programs, pharmacogenomics will exert its impact at the drug discovery stage and will thus appear in products over the longer term.

Genetic variation: a diagnostic basis for pharmacogenomic testing

Despite the 99.9% genetic identity between two randomly chosen individuals, phenotype can still vary considerably in terms of physical features, disease susceptibility as well as drug response. While the statements of some industry leaders that up to 85% of the variance in patient reaction to drugs can be ascribed to genes may be controversial (5), at least some of the variation in absorption, distribution, metabolism, and excretion of a medicine between individuals can clearly be attributed to the 0.1% genetic difference.

This genetic variation can take a number of forms, from changes in a single nucleotide to insertions or deletions of longer sequences. The most common (and...