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Tailoring Drugs to Your DNA

 

Written By: Christina Johnson

One-size-fits-all may be OK for socks, but for medications with potentially life-threatening side effects the approach has holes.

A person’s age, weight, ethnicity, diet and health status can all influence how the body metabolizes and reacts to a medication.

More intriguingly, two people of the same gender, age and ethnicity may have vastly different responses to the same drug because of minute variations in inherited traits. Down in our DNA, we really are like snowflakes.

Enter the age of pharmacogenomics and the study of how tiny differences in our genes can make some drugs dangerous and others virtually useless at doses normally given.

“Pharmacogenomics uses genetic information to help us predict drug efficacy and toxicity,” said Grace Kuo, PharmD, PhD, professor of clinical pharmacy and associate dean for academic clinical affairs at UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences. “Right now we mostly use genetic information to protect patients from toxicity and allergies and to optimize a drug’s dose to achieve an ideal therapeutic target.”

Genetics capsule

But just how big of a difference does a person’s double-helix of DNA make?

Among the more extreme examples is for the drug Ziagen (abacavir sulfate), an HIV medication administered to patients who have not responded to first-line-of-defense treatments.

Ziagen slows replication of the HIV virus, thus lowering the amount of the virus in the bloodstream, but for people who have a gene variation called HLA-B*5701, the drug can cause a potentially lethal allergic hypersensitivity reaction. The FDA now requires a black box warning for the medication and recommends that any patient who is a candidate for taking Ziagen have a genetic test before the first dose is administered.

“We used to have a wait and see attitude,” said Kuo, who is also an associate adjunct professor with the Department of Family and Preventive Medicine at UC San Diego School of Medicine. “We would give patients a drug and ask them to come back a month later to see how they had responded to the therapy. You can imagine the improvement.”

Another less dramatic example is the drug Plavix (clopidogrel bisulfate), an antiplatelet medication often given to people with acute coronary syndrome or who have suffered a recent heart attack or stroke.

Certain enzymes in the liver (known as CYP450 enzymes) metabolize the drug and it is these metabolites – not the drug itself – that have a therapeutic effect in the body, inhibiting platelet aggregation.

People with certain alleles (alternative forms of a gene that arise by mutation and are found in the same place on a chromosome) have been found to be poor metabolizers of the drug. For these people, the medication has little therapeutic value.

“Here at UC San Diego Health, we give a platelet aggregation test before Plavix is administered,” said Kuo, who is the director of the San Diego Pharmacist Resource and Research Network and also the director of the university’s
Pharmacogenomics Education Program.  “We can predict who will need a higher dose and who will need an alternative antiplatelet. The testing helps add greater precision to treatments.”

Kuo estimates that there are now more than 100 FDA-approved drugs with known genomic-dependent interactions affecting drug efficacy and toxicity, but she said many hospitals don’t have access to labs that can make use of genetic information and the equipment for genetic testing remains expensive.

Nonetheless, “changes are on the horizon,” she said.

The cost of sequencing an entire human genome is now less than $1,000, according to the National Institutes of Health - the first sequenced human genome, completed in 2003, cost about $400 million.

If the price continues to drop, it may be feasible to start sequencing newborns in the first week of life, Kuo said. The sequencing data would provide information on a person’s liver enzymes and immune system functions that influence drug toxicity and efficacy. All this could go on file, similar to a person’s vital signs, except genome sequencing only has to be done once.

“Throughout your life, we would be able to say ‘ah, here is your genetic information, we know how that drug will be metabolized,’” she said. “We could tailor the dose and drugs we give people from nearly day one.”


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