Drug Therapy Gets Personal with Genetic Profiling

Pharmacogenetics Holds Great Promise for Improving Prescribing Practices and Avoiding Adverse Effects

Dana Bartlett, MSN, RN

Disclosures

Am Nurs Journal. 2011;6(5):23-28. 

In This Article

Progressing Toward Personalized Drug Therapy

In the simplest sense, the goal of pharmacogenetics is to understand the effects of genetics on drug response. If this can be done, drug inefficacy and adverse effects could be predicted and avoided, and appropriate drugs could always be prescribed in the proper dosages.

Understanding the effects of genetic variations of CYP450 enzymes on drug metabolism is a vital part of this pursuit. Researchers have known for more than 40 years that inherited variations in drug metabolism can profoundly affect a patient's drug response. Consider these examples:

  • Impaired metabolism of the muscle relaxant succinylcholine can lead to profound adverse effects.

  • Phenformin was developed in the 1970s as an option for treating noninsulin-dependent diabetes mellitus. But an unacceptably high percentage of patients (1 in 4,000) developed metabolic lactic acidosis, which has a mortality of 50% to 70%. In 1977, phenformin was banned in this country; research later showed a powerful genetic polymorphism caused a defect in its metabolism.

Although the concept of personalized drug therapy is attractive, the literature indicates that reaching this goal is far from simple. Prescribing drugs based on genetic knowledge would require an understanding of the genetic basis of and influence on the disease or disorder being treated. It would entail development of tests that provide fast, accurate genetic information about drug metabolism—and this information would need to be easy to interpret and clinically useful. It also would require comprehensive knowledge of how genetics influences all aspects of pharmacokinetics—drug absorption, distribution, metabolism, and elimination.

Genetics also can influence the drug target in the body (pharmacodynamics). Drugs work by affecting the activity of enzymes or receptors. For instance, genetic polymorphisms exist for the beta1-adrenergic receptor gene ADRB1 that influence a patient's response to beta blockers. This may explain why African-Americans, who have a lower frequency of the Arg389 allele that affects the body's reaction to beta blockers, don't respond to beta-blocker therapy as well as whites. Clearly, synthesizing pharmacodynamic, pharmacokinetic, and pharmacogenomic information and translating this knowledge into clinical practice pose a huge challenge.

The Psychotropic Drug Example

A review of pharmacogenetic information on psychotropic drugs illustrates this difficulty. CYP450 enzymes (especially CYP2D6) are important metabolizers of virtually all selective serotonin reuptake inhibitors (SSRIs), which are used to treat major depressive disorder. These enzymes also are important metabolizers of many other drugs used to treat psychotic disorders, schizophrenia, and other types of depression. Polymorphism of these enzymes can affect the metabolism of such psychotropic drugs as aripiprazole, haloperidol, and risperidone.

But most data on the effects of CYP450 polymorphism and metabolism of these drugs come from animal studies, in vitro studies, single-dose pharmacokinetic studies, or drug-interaction studies. Studies of CYP2D6 polymorphism and extrapyramidal side effects and movement disorders (for instance, tardive dyskinesia and parkinsonism) linked to certain psychotropics have shown contradictory results. And although CYP450 enzymes metabolize SSRIs, a comprehensive review failed to find a strong link between genetic variants in these enzymes and differences in SSRI efficacy or tolerability. Tests used to detect these polymorphisms were sensitive and accurate, but the authors concluded the data weren't clinically useful. Other researchers drew the same conclusion after reviewing the pharmacogenetic response to risperidone and other atypical antipsychotics. They speculated that drug-metabolizing enzyme activity may play only a minor role in the clinical response to these drugs.

Genotyping

One goal of pharmacogeneticists is to develop the ability to quickly and accurately determine a patient's genotype, which would allow detection of all clinically important CYP450-enzyme polymorphisms. Right now, this isn't possible.

The FDA-approved AmpliChip CYP450 test can detect many CYP2D6 and CYP2C19 polymorphisms. These two enzymes metabolize approximately 25% of all commonly used drugs, including many antidepressants, beta blockers, analgesics, anticonvulsants, benzodiazepines, and proton-pump inhibitors. The test can predict if a patient will be a poor, intermediate, extensive, or ultra-rapid metabolizer of CYP2D6 and CYP2C19. Although AmpliChip holds promise in helping to prevent adverse drug reactions, it can only predict—not confirm—a patient's metabolizing status. And despite its 99% sensi-tivity and 100% specificity, some researchers note that studies of its effectiveness have been poorly designed and lack statistical power.

Pharmacogenetic Drug Testing

Some drugs have been relabeled (with FDA input) to include pharmacogenetic information, but this information isn't specific enough to guide treatment recommendations. FDA-approved pharmacogenetic tests exist for only three drugs—voriconazole, atomoxetine, and irinotecan. And these tests predict increased plasma drug concentrations that may be linked to an increased incidence of adverse effects—nothing else.

Obviously, the most serious issues surrounding pharmacogenetic testing—clinical validity and utility—are still far from resolved. What's more, other factors, such as concomitant medications, age, tobacco use, and diet, can affect drug metabolism, too. These variables haven't been completely factored into pharmacogenetic testing for drug metabolism and SNPs. Although much work has been done, no studies have used pharmacogenetic information to adjust drug dosages.

In addition, quick and accurate testing that provides reliable, clinically valid and useful information is lacking. For example, the AmpliChip test can accurately identify breastfeeding mothers who are rapid codeine metabolizers. These women excrete larger amounts of morphine (the codeine metabolite) in breast milk, which can adversely affect breastfeeding infants. But evidence that this genetic variation can be used as a clinical tool to avoid adverse effects in infants is limited.

So despite the large amount of pharmacogenetic information available, scientists aren't sure how to use it. The FDA requires genetic testing only for four drugs—cetuximab, trastuzumab, maraviroc, and dasatinib—before therapy can begin. Such testing is recommended but not required for carbamazepine, valproic acid, and mercaptopurine. For other drugs, such as tretinoin and isoniazid, information about genetic variations and drug response is available, but we don't know how to use it.

What types of tests could be used to make pharmacogenetic information applicable to clinical situations? And who should perform them? Only six FDA-approved pharmacogenetic tests are available to check for genetic variations, and they address just five drugs. Yet more than 1,300 tests that don't require FDA approval are available for genetic testing. These tests are complex to perform, but laboratories aren't required to demonstrate skill in this area. Also, few laboratories offer pharmacogenetic testing for clinicians, and turnaround time for results may be too long. Finally, although some tests may be covered by insurance plans, many are considered experimental and aren't covered; few patients could afford to pay for them out of pocket.

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