What will be the role of pharmacogenetics in evaluating drug safety and minimising adverse effects?

In the US, adverse drug reactions (ADRs) rank between the fourth to sixth leading cause of death, ahead of pneumonia and diabetes mellitus. An important reason for the high incidence of serious and fatal ADRs is that the existing drug development paradigms do not generate adequate information on the mechanistic sources of marked variability in pharmacokinetics and pharmacodynamics of new therapeutic candidates, precluding treatments from being tailored for individual patients. Pharmacogenetics is the study of the hereditary basis of person-to-person variations in drug response. The focus of pharmacogenetic investigations has traditionally been unusual and extreme drug responses resulting from a single gene effect. The Human Genome Project and recent advancements in molecular genetics now present an unprecedented opportunity to study all genes in the human genome, including genes for drug metabolism, drug targets and postreceptor second messenger machinery, in relation to variability in drug safety and efficacy. In addition to sequence variations in the genome, high throughput and genome-wide transcript profiling for differentially regulated mRNA species before and during drug treatment will serve as important tools to uncover novel mechanisms of drug action. Pharmacogenetic-guided drug discovery and development represent a departure from the conventional approach which markets drugs for broad patient populations, rather than smaller groups of patients in whom drugs may work more optimally. Pharmacogenetics provides a rational framework to minimise the uncertainty in outcome of drug therapy and clinical trials and thereby should significantly reduce the risk of drug toxicity.