For a long time, scientists and physicians have known and been able to act upon the fact that there is a genetic component to disease. That a person’s genetic makeup also plays a major role in determining which drugs will be effective for them in fighting certain diseases has been well known for decades. Now, doctors can pinpoint some of those genetic components to determine how an individual will respond to certain medications by using an FDA-approved genetic test.

This class of genetic testing, called pharmacogenetics, is an excellent example of how genomics is leading toward personalized medicine. Pharmacogenetics will enable rational administration of drugs, reduce “trial and error,” and reduce adverse drug reactions because how a patient will react to a drug can be learned before that drug is administered.

A number of proteins are involved, especially in the liver, small intestine and brain, in metabolizing drugs. A subset of these proteins is called the cytochrome P450 (CYP450) superfamily of enzymes. CYP450 proteins, just like all proteins, are coded for by genes. There are tests to define important, relevant DNA sequences in many genes involved in drug metabolism, for example the genes for CYP450 2C9, CYP450 2C19, CYP450 2D6, n-acetyl transferase, and thiopurine methyltransferase. CYP2D6 metabolizes about 25% of all clinically used medications, including dextromethorophan, ß-blockers, antiarrhythmics, antidepressants, and morphine derivatives.

The test that received FDA clearance is one that may be used to analyze an individual’s relevant genetic sequences in the CYP2D6 and CYP2C19 genes. Based on the sequence of DNA at certain key points in these genes, laboratory scientists can provide information to physicians and pharmacists (especially hospital-based pharmacists caring for inpatients) that helps predict how a patient will respond to administration of a drug metabolized by either CYP2D6 or CYP2C19. For example, this pharmacogenetic information helps determine if a patient will metabolize these drugs unusually slowly, unusually rapidly, normally, or not at all.

Performing such testing may be important because if someone metabolizes a drug poorly or not at all, they will not receive the same therapeutic benefits from the drug that the normal metabolizer does. Even worse, they may suffer an adverse drug reaction because of buildup of unmetabolized drug in their system. Consequently, they could remain ill or become even sicker. Ultra-rapid metabolizers may need more than the usual dose to obtain a therapeutic benefit. If a doctor knows that someone is a poor metabolizer for a particular drug due to such pharmacogenetic testing, alternative therapies may be considered to manage the patient’s disease or illness.

The largest body of evidence for using the CYP450 test exists for certain psychiatric drugs used to treat conditions such as depression and schizophrenia. Psychiatrists therefore may be among the first groups of doctors utilizing this test. While the test received FDA clearance in late 2004, the vendor anticipates its availability in the laboratory medicine marketplace sometime during the middle of 2005.

Sources
U.S. Food and Drug Administration. FDA News: FDA Clears First of Kind Genetic Lab Test. December 23, 2004. Available FTP: http://www.fda.gov/bbs/topics/news/2004/new01149.html.

Interviews with Walter Koch, PhD, Vice President and Head of Research at Roche Molecular Systems, and Tita Forrest, PharmD, Head of Commercial Marketing for Clinical Genomics at Roche Molecular Systems, conducted by Sue Parham on February 16, 2005.

Special Report: Genotyping for Cytochrome P450 Polymorphisms to Determine Drug-Metabolizer Status. Available as PDF: http://www.bcbs.com/tec/Vol19/19_09.pdf