October 15, 2008

 

 Getting the right drug at the right dosage - October 15, 2008

 

 

Personalized medicine brings precision to drug treatment

posted October 1, 2008

 

People vary widely in their response to medications. Some may develop few if any adverse reactions to a drug whereas others may have a severe adverse reaction when given the drug at the same dosage. Genetic variations are one of the primary factors accounting for the wide range in drug response. Information about these genetic variations is not yet widely used to guide drug treatment in day-to-day clinical practice, however, and the cost of determining these genetic variations is often not covered by health insurance plans.

Personalized medicine offers an opportunity for physicians to improve clinical care by using diagnostic tests to predict which drugs and dosages will work best for individual patients. These tests can identify genetically based variations in metabolic pathways, cancer cell markers, or viral receptors. This targeted approach to care is based on advances in the field of pharmacogenomics—the study of how genetic variations affect an individual's response to drugs.

Medco Health Solutions, the pharmacy benefits manager for the AVMA Group Health and Life Insurance Trust, has existing collaborations with Mayo Clinic and Laboratory Corporation of America for pharmacogenomic testing and recently entered into a research partnership with the Food and Drug Administration to study genetic testing and the impact of genetics on the efficacy of prescription drugs. Under the partnership, Medco and the FDA will jointly develop research projects, programs, and strategies in the area of pharmacogenomics, collectively aimed at improving patient health and quality in the delivery of care.  

Pharmacogenomics

Genetic variations influence a person's response to drugs through three primary pathways: metabolic enzymes, drug transporters, and drug receptors.  
  • Metabolic enzymes. A major factor in the bioavailability of a drug is the activity of metabolic enzymes. For example, one of the cytochrome P450 liver enzymes, CYP2D6, is responsible for metabolizing about 25 percent of currently available medications. For many drugs, the primary function of this enzyme is to convert the drug into inactive metabolites. For other drugs, such as codeine and tamoxifen, the enzyme is responsible for converting the drug into its biologically active form. People have genetic variations in the activity of the CYP2D6 enzyme, resulting in four phenotypes—slow metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers. Slow metabolizers may be at increased risk for adverse effects because they take longer to metabolize a drug whereas the same drug may be ineffective for people who metabolize it quickly. (The prevalence of these phenotypes in a Caucasian population is illustrated in the chart on page 1213.)
  • Drug transporters. Genetic variations also affect the activity of cell membrane transporters. For example, the MDR1 gene encodes for p-glycoprotein, a transporter that helps move several types of drugs—including protease inhibitors and some cancer drugs—across cell membranes. Variations in the MDR1 gene can change the amount of p-glycoprotein, reducing the efficacy of the drug or increasing the risk of adverse effects, depending on the role of the transporter.
  • Drug receptors. A patient's genotype or the genetic makeup of a cancerous tumor can affect the response of drug receptors in the body. Biomarker tests for receptor activity can help predict how effective a drug will be in a given patient. For example, tests for HER2/neu in women with breast cancer can help predict the response to trastuzumab. 
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Benefits of testing

Many genetic and biomarker tests are already available to help clinicians predict whether a drug or dosage is likely to be effective—or potentially toxic—for an individual patient. Microarray tests are available to detect genetic variations in many metabolic enzymes, including CYP2D6. Receptor biomarker testing is widely used in the selection of cancer treatment, and viral genotype testing is gaining increased use in the treatment of certain viral infections, such as HIV. For many drugs, product labeling already includes information about the possible impact of genetic variations on drug response, and in some cases, genetic or biomarker testing is recommended as a guide to treatment or dosage selection.

 

Figure 1. Variations in CYP2D6 drug metabolism in a Caucasian population
Phenotype Prevalence Characteristic drug response
Poor metabolizer 7% to 10% Drugs are metabolized very slowly, so they may accumulate to toxic concentrations.
Intermediate metabolizer 10% to 15% Diminished capacity to metabolize drugs. Lower-than-average dosages may be sufficient to achieve therapeutic response.
Extensive metabolizer 73% to 82% Typical rate of drug metabolism.
Ultrarapid metabolizer 1% to 2% Unusually high rate of drug metabolism. Drugs may not reach therapeutic concentrations, so the drugs may be ineffective at standard dosages.

Genetic testing can help determine medication dosages early in treatment and reduce the risk of serious adverse reactions. For example, treatment with warfarin often requires multiple dosage adjustments, given the narrow therapeutic range of the drug and the many factors—including genetic variations—that affect a patient's response. Inappropriate dosing can lead to serious adverse events such as bleeding or thrombosis, which often require hospitalization.

A recent study published in the journal Clinical Pharmacology & Therapeutics demonstrates that early genotype testing can have a positive impact on warfarin treatment in controlled clinical settings. Patients in a genotype-adjusted treatment group reached therapeutic concentrations more quickly, spent more time in the therapeutic range, and experienced fewer minor bleeding events compared with patients in a control group.

If similar benefits from genetic testing can be demonstrated in community practice settings, the potential savings could be substantial in human and financial terms. The American Enterprise Institute-Brookings Joint Center predicted in a November 2006 report that using genetic information to prescribe warfarin could reduce health care spending by about $1.1 billion each year, while preventing about 17,000 strokes and 85,000 serious bleeding incidents.  

The future of care for humans and animals

Personalized medicine has begun to revolutionize the care of humans and is also likely to revolutionize the care of animals. There is a growing body of evidence that genetic variations in many species are associated with clinically important variations in response to drug treatment. Veterinarians recognize that a large percentage of Collies carry a mutation of the MDR1 transporter gene, which lowers p-glycoprotein concentrations and raises the risk of neurologic toxicosis in response to commonly used drugs such as ivermectin. Genetic variations in metabolic enzymes also have been observed in several animal species, and these variations can impact drug response. Over time, veterinary medicine is likely to benefit from more targeted drug treatment based on diagnostic testing for genetic variations in response. 
 

Broader use of genetic testing raises legal, ethical, and technologic issues for the storage and retrieval of personal genetic information. Widespread use of genetic testing will depend on several factors, including stronger evidence for the clinical and economic benefits, easy access to genetic testing, incorporation of genetic testing into clinical practice standards, and integration of this new type of diagnostic testing into health insurance benefits. The AVMA GHLIT will continue to monitor developments in this field.