Doctor Offering Drug Personalized By Genome Test

Using information it has compiled from its Center for Devices and Radiologic Health and the Center for Drug Evaluation and Research (CDER), the FDA late last week published a resource of gene-drug interactions for which he agency feels it has sufficient scientific evidence to help guide treatment decisions.

Understanding a patient’s genotype is becoming an increasingly important tool in determining appropriate disease treatment therapies. This information is often used for drugs developed to target certain mutations, but the FDA has recently compiled a list of ‘regular’ drugs known to interact either negatively or differently in patients with certain genetic profiles. This information can be invaluable to determining why certain drugs can work well to treat some patients, yet may be ineffective, or even cause an adverse reaction in others.

There are three categorizes treating physicans should be aware of to understand drug-genotype interactions: pharmacogenetic interactions for which the data support therapeutic management; pharmacogenetic interactions for which the data indicate a potential impact on safety or response; and pharmacogenetic interactions for which the data demonstrate a potential impact on pharmacokinetic properties.  All three are interactions that the patient and the provider should be aware of.

When a health care provider is considering prescribing a drug, knowledge of a patient’s genotype may be used to aid in determining a therapeutic strategy, determining an appropriate dosage, or assessing the likelihood of benefit or toxicity.

The FDA has published gene-drug interaction tables for this purpose, but does not necessarily advocate the use of genetic testing prior to drug prescribing for the corresponding medication, unless the test is a companion diagnostic.

The FDA believes it has sufficient scientific evidence to suggest certain genetic variants are likely to have altered the metabolism of many drugs, and in certain cases, result in different therapeutic results, including a difference in risk of adverse events. They have summarized these results in three tables.

In some cases, a specific genetic variant was found to affect the metabolism of different drugs. In cases where the association was limited to specific genetic variants and did not apply to all individuals with the genotype-inferred phenotype, the specific variants are listed. In cases where individual genetic variants are not listed in the table, the FDA believes there is sufficient scientific evidence to support the described association for the genotype-inferred phenotype, provided specific genetic variants are determined to confer the genotype-inferred phenotype based on scientific evidence.

For example, when considering individuals who have the genotype for poor and intermediate metabolization of CYP2C19, they have higher systemic active metabolite concentrations, higher adverse reaction risk, and dosage adjustments are recommended when taking clobazam.  Sufficient scientific evidence supports this claim, with respect to the *2 allele:

  • The functionality of the *2 variant is known, i.e., the *2 variant results in a loss of CYP2C19 enzyme function, and
  • *1/*2 confers an intermediate metabolizer phenotype, and *2/*2 confers a poor metabolizer phenotype.

Specific information that regards therapeutic management is provided for some pharmacogenetic associations, but most of the associations listed have not been evaluated in terms of the impact genetic testing will have on clinical outcomes, such as improved therapeutic effectiveness or increased risk of specific adverse events. In addition, clinical studies, if available, may only have linked genetic variation to a drug’s pharmacokinetics (i.e., the way in which the drug is metabolized), and differences in drug efficacy or safety across different genotype subgroups may not be known. If no statements related to efficacy or toxicity are mentioned, the scientific evidence the FDA reviewed was considered insufficient to support such associations.

The FDA stated they recognize practitioners will take into account different sources and strengths of evidence, and will make prescribing decisions based on their judgment about which treatments are appropriate for individual patients. In particular, each patient’s genetic makeup is only one of many factors that may impact drug concentrations and response, highlighting the fact that information provided in this new publication is limited to certain pharmacogenetic associations only and does not provide comprehensive information needed for safe and effective use of a drug.

Health care providers should refer to FDA-approved labeling for prescribing information, including monitoring instructions and information on other factors that may affect drug concentrations, benefits, and risks.  The impact of specific genetic variants or genetic variant inferred phenotypes on the safety or response of the corresponding drug has not been established, but this new publication can help guide physician treatment, in case there is any concern with regards to how a patient will respond to a specific drug.

The information provided in these tables is intended primarily for prescribers, and patients should not adjust their medications without consulting their prescriber.  This information is also intended to shed light on the impact different genetic variations can have on medication that is already in the marketplace, so an abnormal reaction to the expected response can be scientifically assessed.

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