LAS VEGAS — A session on pharmacogenomics at the American Academy of Physician Assistants meeting here began with a lawsuit.
In 2014, the Attorney General in Hawaii filed suit against drugmakers Bristol-Myers Squibb and Sanofi, charging the companies had evidence for years that clopidogrel (Plavix) was less effective among patients of Pacific Island descent, but ignored those signs and marketed the drug anyway.
It’s estimated that 25% of Hawaiians could be affected by a genetic variant that reduces the efficacy of Plavix, according to Melissa Murfin, PA-C, PharmD, of Elon University in North Carolina — and research has shown that mortality rates were twice as high among Pacific Islanders compared with Caucasians when giving Plavix following acute myocardial infarction (2.6% versus 4.8%), she noted.
Murfin argued this example signals to clinicians that having a mechanism to prevent adverse events, including a lack of efficacy for the the drugs they prescribe, is important.
Clinicians need to understand that the research used to approve a drug may not reflect the population that takes the drug, she said. For instance, 95% of participants in the CAPRIE trial, which was completed in the late 1990s and compared clopidogrel to aspirin, were Caucasian.
Rather than expecting the drug company to tell how best to prescribe these medications and to whom, “It kind of falls on us … as clinicians we need to figure that out for ourselves,” she said.
Pharmacogenomics — using an individual’s complete genetic profile to develop personalized treatment, which is often referred to as personalized or precision medicine — offers a way forward, Murfin said. This isn’t a new field; oncologists have used tumor markers to prescribe the right chemotherapy drugs, and those treating HIV patients have used genetic markers to pre-determine life-threatening sensitivity to certain medications.
Now primary care doctors are realizing that even more commonly used medications are also impacted by genetic variations, and that drugs are processed differently by different people, she said.
Pharmacokinetics — “what the body does to the drug,” she explained — covers the absorption, distribution, metabolism, and excretion of drugs. The most significant factor for clinicians involves how drugs are metabolized.
Metabolizing enzymes can impact a drug’s therapeutic response and even lead to adverse drug reactions. For example, when metabolic enzymes aren’t functioning properly, the end result could be greater drug toxicity. Alternatively, if a pro-drug isn’t metabolized properly it may not get converted to its active form and lose efficacy.
One of the most well-known metabolic factors to interfere with several medications is the cytochrome P450 pathway, a metabolic system in the liver. Patients generally fall into one of four categories regarding how their metabolic activity in this pathway, Murfin said:
- Ultra-rapid metabolizers: patients with more than one copy of a functional allele will process drugs very quickly
- Extensive (normal) metabolizers: patients with two alleles with full function, or one that is fully functional and one that is non-functional
- Intermediate metabolizers: those who may or may not have any clinically significant changes
- Poor metabolizers: patients with no functional allele may have difficulty metabolizing a drug leading to increased toxicity or less efficacy
Clinicians can now test for the genes that have the potential to contribute to these different responses, she added.
Returning to the Plavix example, Murfin noted that the reason the drug is less effective in its antiplatelet activity is due to individuals being CYP2C19 poor metabolizers, who are homozygous for non-functional alleles of the CYP2C19 gene. The FDA has now added a warning label to indicate such differences.
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