Introduction
Pharmacogenomic reports contain a lot of useful information. Sometimes there is so much information the report can seem overwhelming. To overcome this issue and to increase the clarity of the results for both healthcare providers and patients, the GeneSight test employs a user-friendly software-based product to report the results in an easy-to-read way. The GeneSight report categorizes medications into intuitive, color-coded categories based on an individual’s genetic results. These include the green “Use as Directed,” yellow “Moderate Gene-Drug Interaction,” and red “Significant Gene-Drug Interaction” categories.
What are clinical considerations and what is their clinical significance?
All medications start out in the green category on the GeneSight test. Based on an individual’s genetic variation, a medication may be moved out of this category, and into the yellow or red category, depending on how significantly the variation is expected to impact response. When this happens, the medication is labeled with one or more of the ten possible clinical considerations, which can help guide treatment decisions and provide information about how medications affected by genetic variation might be best used.
How do I interpret each clinical consideration?
CLINICAL CONSIDERATIONS:
1: Serum level may be too high, lower doses may be required.
2: Serum level may be too low, higher doses may be required.
3: Difficult to predict dose adjustments due to conflicting variations in metabolism.
2: Serum level may be too low, higher doses may be required.
3: Difficult to predict dose adjustments due to conflicting variations in metabolism.
Clinical considerations 1 and 2 reflect an issue with how the medication is metabolized. This means that the individual has variation in one or more of their pharmacokinetic genes. This may affect how much medication is in an individual’s system and may require a lower or higher dose, respectively. Clinical consideration 3 indicates that there is conflicting variation in the genes that metabolize that medication (e.g. for two genes that affect the medication’s metabolism, the patient is ultrarapid for one and poor for the other), thus making it difficult to recommend a dose adjustment.
4: Genotype may impact drug mechanism of action and result in reduced efficacy.
Medications labeled with clinical consideration 4 are affected by a pharmacodynamic gene, and thus reflect an issue with the drug’s mechanism of action. Variation in these genes predicts a reduced response to certain medications. Since pharmacodynamic genes do not affect metabolism, it is unlikely that adjusting the dose will improve efficacy.
* Clinical consideration 5 is not currently in use in the United States.
6: Use of this drug may increase risk of side effects.
Clinical consideration 6 indicates that an individual has an increased risk for side effects when taking this medication. This can be the result of high levels of medication in the system or an effect caused by the drug’s mechanism of action.
7: Serum level may be too low in smokers.
Clinical consideration 7 only applies if the individual is a smoker, and indicates that smoking may increase the metabolism of that medication. This is because smoking induces CYP1A2, which is involved in the metabolism of several medications.1–4 The reaction is not caused by the nicotine, but rather by inhaling the burning hydrocarbons.3 When you see clinical consideration 2 coupled with clinical consideration 7, it means that if the individual is a smoker, they will metabolize that medication even more quickly than someone who is an ultrarapid metabolizer and does not smoke.
8: FDA label identifies a potential gene-drug interaction for this medication.
9: Per FDA label, this medication is contraindicated for this genotype.
9: Per FDA label, this medication is contraindicated for this genotype.
When medications are labeled with clinical consideration 8, it alerts the healthcare provider and patient that the FDA has made a statement in the package insert that may have pharmacogenomic implications for a person with this genotype taking this medication. Clinical consideration 9 indicates that the FDA has declared this medication contraindicated for a person with this genotype.
10: This medication does not have identified or clinically proven genetic markers which allow it to be categorized.
Clinical consideration 10 is associated with medications in the gray “No Proven Genetic Markers” category, meaning that genetic markers have not yet been discovered to reliably predict which genes are involved in the metabolism or therapeutic efficacy of these medications. Due to this lack of evidence, we are not currently able to categorize them or provide actionable recommendations.
Conclusions
Clinical considerations provide valuable information about why a medication does not fall in the green category. Healthcare providers can rely on these to help them think about how to potentially use a medication that is affected by genetic variation. Clinical considerations can also be used to help guide discussions with patients about treatment decisions.
References
- Dobrinas, M. et al. Impact of smoking, smoking cessation, and genetic polymorphisms on CYP1A2 activity and inducibility. Clin. Pharmacol. Ther. 90, 117–125 (2011).
- Kroon, L. A. Drug interactions with smoking. Am. J. Heal. Pharm. 64, 1917–1921 (2007).
- Zevin, S. & Benowitz, N. Drug Interactions with Tobacco Smoking. Clin. Pharmacokinet. 36, 425–438 (1999).
- Tantcheva-Poór, I., Zaigler, M., Rietbrock, S. & Fuhr, U. Estimation of cytochrome P-450 CYP1A2 activity in 863 healthy Caucasians using a saliva-based caffeine test. Pharmacogenetics 9, 131–144 (1999).