D. Baker
Jun 1, 2003
Citations
0
Influential Citations
1
Citations
Journal
Hospital Pharmacy
Abstract
Most of the information we know about the mechanism of action, pharmacokinetics, effectiveness, and safety of medications is based on controlled clinical trials with defined patient population. These studies provide us with general demographics but usually do not provide information about genetic variations within the study population that might have influenced some or all of the study results. Clinical drug research aims ultimately at identifying the cause of a particular condition and then designing an agent targeted at this cause that will work in all patients with minimal toxicity. However, it has long been recognized that some individuals respond quite differently to certain medications. This type of observation was the first hint that the differences in drug response, drug interactions, and elimination between individuals, genders, and races may be explained by differences in the genetic code between individuals. While this was no surprise, it opened up a whole new world of scientific exploration and drug development. Pharmacogenomics is the application of knowledge about drug targets, pharmacology, pharmacokinetics, and genetic information to clinical practice. Genetic differences explain why some patients do not respond to certain medications or are at increased risk of toxicity because of higher serum concentrations of the active drug or its metabolites. A good example of decreased effectiveness is codeine therapy in a patient who has lower cytochrome P450 2D6 activity. In these patients, codeine is not converted to its active metabolite (morphine). Thus these patients do not benefit from the analgesic activity generally associated with codeine therapy. Decreased metabolism of a drug by various enzyme systems (eg, CYP 2D6, CYP 3A4) can cause elevated serum and tissue concentrations, increasing the chances that a patient may develop a toxicity at a normal dose or adequate pharmacologic effects at lower doses. The polymorphisms that can occur in nucleotides may make it impossible to design a drug that is safe and effective in all patients. However, a better understanding of these differences and the ability to identify particular polymorphisms in genes may allow us to identify patients who might not respond to a particular drug or who may be at increased risk for drug-related toxicities before the drug is administered. It could also allow practitioners to tailor the dose of a medication based on the patient’s genetic code instead of just their weight and age. The importance of including this type of information in drug product labeling was reviewed by the Food and Drug Administration’s Clinical Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical Science on April 23, 2003. It was the feeling of this subcommittee that pharmacogenetic variations in enzymes, transporters, or receptors with clinical outcomes should be included in drug labeling. The subcommittee also agreed that if the genotype associated with a variation can be identified with a particular test, then this information should be included in the labeling. These recommendations are appropriate given our level of knowledge and the rapid progress that is being made in pharmacogenomics. Let’s hope that the pharmaceutical industry embraces these recommendations soon and that the manufacturers of these tests do not overprice their products. The ability to use this type of knowledge to tailor drug therapy for our patients and decrease the risk of preventable adverse drug reactions would be highly beneficial. Therefore, it would be appalling if the use of this knowledge was prohibited by the cost of testing.