A lead-in question is: What does the FDA use to ensure there is sufficient scientific evidence in pharmacogenetics?
When evaluating if a gene-drug association is supported, FDA believes it is important to ensure that there is sufficient scientific evidence to support:
- The relationship between the detected genetic variant and as appropriate, diplotypes, and the affected subgroup, and
- The association between the affected subgroup and the claimed gene-drug interaction.
As it turns out, there are many Pharmacogenetic Associations for which the Data Demonstrate a Potential Impact on Pharmacokinetic Properties Only
The impact of these genetic variants or genetic variant inferred phenotypes on the safety or response of the corresponding drug has not been established.
| Drug | Gene | Affected Subgroups+ | Description of Gene-Drug Interaction |
| Amitriptyline | CYP2D6 | ultrarapid, intermediate, or poor metabolizers | May alter systemic concentrations. |
| Amoxapine | CYP2D6 | ultrarapid, intermediate, or poor metabolizers | May alter systemic concentrations. |
| Atorvastatin | SLCO1B1 | 521 CC (poor function transporters) | May result in higher systemic concentrations. |
| Avatrombopag | CYP2C9 | intermediate or poor metabolizers | Results in higher systemic concentrations. |
| Carisoprodol | CYP2C19 | poor metabolizers | Results in higher systemic concentrations. Use with caution. |
| Clomipramine | CYP2D6 | ultrarapid, intermediate, or poor metabolizers | May alter systemic concentrations. |
| Darifenacin | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. |
| Desipramine | CYP2D6 | ultrarapid, intermediate, or poor metabolizers | May alter systemic concentrations. |
| Dexlansoprazole | CYP2C19 | intermediate or poor metabolizers | Results in higher systemic concentrations. |
| Diazepam | CYP2C19 | poor metabolizers | May affect systemic concentrations. |
| Dolutegravir | UGT1A1 | poor metabolizers | Results in higher systemic concentrations. |
| Donepezil | CYP2D6 | ultrarapid or poor metabolizers | Alters systemic concentrations. |
| Doxepin | CYP2C19 | intermediate or poor metabolizers | Results in higher systemic concentrations. |
| Doxepin | CYP2D6 | ultrarapid, intermediate, or poor metabolizers | May alter systemic concentrations. |
| Elagolix | SLCO1B1 | 521 CC (poor function transporters) | Results in higher systemic concentrations. |
| Escitalopram | CYP2C19 | ultrarapid, intermediate, or poor metabolizers | May alter systemic concentrations. |
| Esomeprazole | CYP2C19 | poor metabolizers | Results in higher systemic concentrations. |
| Fesoterodine | CYP2D6 | poor metabolizers | Results in higher systemic active metabolite concentrations. |
| Fluvoxamine | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. Use with caution. |
| Galantamine | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. Titrate dosage based on tolerability. |
| Hydralazine | Nonspecific (NAT) | poor metabolizers | Results in higher systemic concentrations. |
| Ibuprofen | CYP2C9 | poor metabolizers or *3 carriers | May result in higher systemic concentrations. |
| Imipramine | CYP2D6 | ultrarapid, intermediate, or poor metabolizers | May alter systemic concentrations. |
| Metoprolol | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. |
| Mirabegron | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. |
| Nebivolol | CYP2D6 | poor metabolizers | May result in higher systemic concentrations. |
| Nortriptyline | CYP2D6 | ultrarapid, intermediate, or poor metabolizers | May alter systemic concentrations. |
| Omeprazole | CYP2C19 | intermediate or poor metabolizers | Results in higher systemic concentrations. |
| Paroxetine | CYP2D6 | ultrarapid, intermediate, or poor metabolizers | May alter systemic concentrations. |
| Propranolol | CYP2D6 | poor metabolizers | May affect systemic concentrations. |
| Protriptyline | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. |
| Rabeprazole | CYP2C19 | poor metabolizers | Results in higher systemic concentrations. |
| Raltegravir | UGT1A1 | *28/*28 (poor metabolizers) | Results in higher systemic concentrations. |
| Risperidone | CYP2D6 | poor metabolizers | Alters systemic parent drug and metabolite concentrations. |
| Rosuvastatin | SLCO1B1 | 521 CC (poor function transporters) | Results in higher systemic concentrations. |
| Tamoxifen | CYP2D6 | intermediate or poor metabolizers | Results in lower systemic active metabolite concentrations. The impact of CYP2D6 intermediate or poor metabolism on efficacy is not well established. |
| Tamsulosin | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. Predicted effect based on experience with CYP2D6 inhibitors. Use with caution. |
| Trimipramine | CYP2D6 | ultrarapid, intermediate, or poor metabolizers | May alter systemic concentrations. |
The table describes gene-drug interactions and indicates specific affected subgroup(s) to which the interaction applies. The affected subgroup(s) may be carriers of a specific genetic variant (e.g., HLA-B*15:02), or a genotype-inferred phenotype, ultrarapid, normal, intermediate, or poor metabolizers/function transporters of a drug metabolizing enzyme/drug transporter. Normal metabolizers or normal transporters do not have genetic variants that are expected to impact metabolism or transport function. In general, ultrarapid metabolizers have two or more copies of a genetic variant that increases metabolic function; intermediate metabolizers or reduced function transporters are individuals who have one or two copies of a genetic variant that reduces the ability to metabolize or transport a drug; and poor metabolizers or poor function transporters are individuals who generally have two copies of a genetic variant that results in little to no ability to metabolize or transport a drug.
In some cases, a specific genetic variant may affect the metabolism of different drugs in different ways. In cases where the association is limited to specific genetic variants and does not apply to all individuals with the genotype-inferred phenotype, the specific variants are provided in the table. In cases where individual genetic variants are not listed in the table, FDA believes there is sufficient scientific evidence to generally support the described association for the genotype-inferred phenotype subgroup, provided specific genetic variants are determined to confer the genotype-inferred phenotype based on sufficient scientific evidence.
For example, when considering, as described in the table, that poor and intermediate metabolizers of CYP2C19 have higher systemic active metabolite concentrations, higher adverse reaction risk, and dosage adjustments are recommended when taking clobazam, sufficient scientific evidence supports the following, 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.
