Pharmacogenetics: From research to clinical implementation

In today's medicine, patients are receiving drug therapy using dosages which have been established as the best dose, determined as an average in a large group of individuals. Although we take for granted that patients behave in a similar way on drug therapy, it is well known from clinical practice that interindividual variations exists in drug response. For drugs with a narrow therapeutic window, and/or drugs with potentially severe or even lethal side effects, this constitutes a major problem. Adverse Drug Reactions (ADRs) affect 2 million patients/year in the USA, resulting in 100,000 deaths annually. This makes ADRs the 5th most frequent cause of death. In fact, 7% of all hospitalizations are caused by ADRs (1-4). On the other side, of all drugs, only 25-60% are effective. A major part of the variability in drug response is thought to be the consequence of substantial interindividual variability in drug metabolism. This metabolism of drugs by the liver is partly determined by hereditary factors, with variant alleles of the same gene potentially encoding active, inactive or ultra-active enzyme activities. Using pharmacogenetics, being DNA analyses in genes encoding drug metabolizing enzymes and drug transporters, the challenge is to identify patients with these genetic variants, thereby predicting their corresponding metabolic capacity. With this information, genotype adjusted dosages, or another drug can be prescribed. This Personalized Medicine approach can improve healthcare by decreasing ADRs and improving effectivity of treatment, a topic of interest for patients and healthcare professionals with, in addition, substantial economical implications as well. The current challenge is therefore to characterize to what degree these genetic polymorphisms affect drug therapy. This would enable the identification of those pharmacogenetic markers that could help in routine clinical practice to explain, or preferably predict aberrant reactions to common drug therapies.