Pharmacogenomics and TDM May Decrease Adverse Drug Reactions

February 13, 2007

February 13, 2007 (New Orleans) – Results of a study evaluating the clinical effect of genotyping chronic pain patients on analgesic therapy suggest that genotyping along with use of therapeutic drug management (TDM) may increase therapeutic efficiency and improve patient outcomes by reducing adverse drug reactions (ADRs).

A study looking at this combination approach was presented here at the American Academy of Pain Medicine 23rd Annual Meeting.

Genetic analysis is now being used more frequently in the selection and modification of patient therapies, the researchers point out. TDM and pharmacogenomics, which examines genetic variations that determine drug response (and can be used to predict type of response), were used in evaluating 61 patients. In addition, a detailed history and physical exam were included, with emphasis on neurological, cognitive, and functional status.

The majority of therapeutic analgesics are metabolized by polymorphic enzymes, such as cytochrome P450 2D6 (CYP2D6); genetic variations in this cytochrome complex can range from complete enzyme deficiency, leading to drug toxicity, to ultrarapid metabolism, which can result in therapeutic failure. It was hypothesized that higher steady-state concentrations (Css) of those drugs remain in poor and intermediate metabolizers, thus making such individuals more subject to ADRs.

In this study, DNA was extracted from whole blood using Puregene (Gentra Systems) DNA isolation kits. CYP2D6 genotyping of alleles and genes selected for different levels of enzyme activity was performed by Pyrosequencing (Biotage). Steady-state plasma concentrations of specific analgesics — methadone, oxycodone, hydrocodone, and tramadol — respective to patient were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS).

The study was led by Paul Jannetto, PhD, professor of pathology and assistant director of toxicology at the Medical College of Wisconsin, in Milwaukee. "Most of the patients were taking at least 1 of these," said Dr. Jannetto, referring to the 4 drugs.

Of the patients who reported ADRs, 80% were shown to have poor CYP2D6 metabolism; in general, these poor metabolizers (PM) had the highest Css, compared with intermediate metabolizers (IM) and extensive metabolizers (EM), who had the lowest Css. Of the 61 patients, 5% were PM, 41% were IM, and 54% were EM.

The results also showed a relationship between Css of oxycodone and pain relief: at plasma concentrations above 15 to 30 ng/mL, there was partial to complete pain relief, while at lower levels, there was no relief.

This was especially significant because "effects at measured drug levels could be seen. This method has potential as a more accurate method of determining dosage," the authors note.

As to the cost of this type of assay, Dr. Jannetto commented, "At one time, a comparable FDA-approved assay cost $400 to run. But with improved technology, the cost is really coming down. Now you can run a panel of drugs for no more than the price of a chem screen, about $23. So cost is not a problem."

Future prospective studies are needed to confirm the clinical utility of using genetic information to therapeutically manage pain. Nancy Bratanow, MD, who was involved in the study as a clinical specialist in pain medicine, told Medscape, "We plan to further investigate the relationship between drug concentration, drug metabolism, toxicity, and side effects."

Frederick Burgess, MD, an anesthesiologist and pharmacologist at Rhode Island Hospital, in Providence, commented on the study for Medscape. "The findings are significant. Such an investigative test might be especially useful when you’re having trouble determining dosage — usually you aim for the intermediate metabolizers. This test might even help determine what drugs to use or aid in determining drug behavior. In the case of methadone, some patients require higher doses. Instead of this being related to drug-seeking behavior, they might in fact be high metabolizers."

American Academy of Pain Medicine 23rd Annual Meeting: Abstract 111.


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