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How Do I Use the Gene-Drug Interaction Chart?

What is the gene-drug interaction chart?
Healthcare providers and patients often inquire about how they can determine which genes affect response to each medication. The gene-drug interaction chart provides supplementary information about which pharmacokinetic genes are involved in the metabolism of each medication. It is not mandatory to refer to the gene-drug interaction chart when using the GeneSight® test to guide patient medication selection. It is simply intended to augment the patient results on the interpretative pages, which serve as the primary resource to help guide treatment decisions.

How do I interpret the gene-drug interaction chart?
The pharmacokinetic genes on the GeneSight report are listed across the top of the chart, and medications are listed in a column on the left side. Any dot (either shaded or unshaded) signifies that the enzyme is involved in the metabolism of the associated medication. A shaded dot means that variation was found in the patient’s genotype that may impact their response to that medication. An unshaded dot indicates that the gene is associated with medication response, but the patient’s genotype is normal. The format of the gene-drug interaction chart is similar to the earlier pages of the GeneSight report where medications are categorized into the green, yellow, and red categories.

Why do I sometimes see shaded dots for medications that are in the green “Use as Directed” category?
When you see shaded dots in the green “Use as Directed” category, it means that although the patient has variation in one or more genes, it is unlikely to impact their response to that particular medication. This could mean that while an enzyme is involved in the metabolism of the medication, its role is not clinically significant enough to warrant a change in dosing. For example, buspirone (Buspar®) is metabolized by CYP3A4 and CYP2D6.1–3 Since CYP2D6 plays a very minor role in Buspar® metabolism, variation in this gene will not likely change the way Buspar® is metabolized, and therefore Buspar® will remain in the green category even when CYP2D6 has a shaded dot.

Another reason a medication in the green category could have shaded dots is that the enzymes involved have opposite phenotypes and therefore compensate for one another. For example, vilazodone (Viibryd®) is metabolized by three different enzymes: CYP2C19, CYP3A4, and CYP2D6.4 In the example below, the patient is ultrarapid for CYP2C19, intermediate for CYP2D6, and extensive (normal) for CYP3A4. Since CYP2C19 and CYP2D6 have phenotypes in opposite directions, the enzymes very likely compensate for one another, and Viibryd® remains in the green category.

Why are there sometimes no dots for medications in the red “Significant Gene-Drug Interaction” category?
In this uncommon situation, the medication does not have any known pharmacokinetic markers but does have pharmacodynamic markers. Since the gene-drug interaction chart includes only pharmacokinetic genes, the medication will not have any dots. Thus, the reason the medication falls in the red category is due to the effect of the pharmacodynamic gene. The only medication on GeneSight Psychotropic that creates this situation is oxcarbazepine (Trileptal®).

Conclusions
The gene-drug interaction chart provides additional information to healthcare providers and patients about which pharmacokinetic genes are involved in the metabolism of each medication. The GeneSight test takes into consideration the unique metabolic pathways and mechanisms of action for each medication and integrates genetic information from all relevant pharmacokinetic and pharmacodynamic genes to categorize medications into the green, yellow, and red categories.

References
1. FDA Label.. Buspirone. (2010).

2. M. Zhu, W. Zhao, H. Jimenez, D. Zhang, S. Yeola, R. Dai, N. Vachharajani, J. M. Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes. Drug Metab. Dispos. 33, 500-507 (2005).

3. N. Raghavan, D. Zhang, M. Zhu, J Zeng, L. C. CYP2D6 catalyzes 5-hydroxylation of 1-(2-pyrimidinyl)-piperazine, an active metabolite of several psychoactive drugs, in human liver microsomes. Drug Metab. Dispos. 33, 203-208 (2005).

4. FDA Label. Vilazodone. (2011).

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