Farmacogenética: Una herramienta imprescindible en la medicina de precisión
Por Mar Benito MSc – Linkedin
Los tests farmacogenéticos junto con la demás información sobre los pacientes y su enfermedad tienen una gran importancia en la terapia farmacológica. El conocimiento del genotipo del paciente se puede utilizar para determinar la estrategia terapéutica, la dosis apropiada, y calcular la probabilidad de beneficio o efectos secundarios.
Las tablas que se presentan a continuación contienen las asociaciones evaluadas por la FDA, en las que se considera que hay suficientes pruebas científicas para sugerir que los grupos de pacientes con ciertas variantes genéticas puedan tener con más probabilidad un metabolismo del fármaco alterado, o efectos terapéuticos diferentes, lo que incluye diferencias en el riesgo de efectos secundarios. El hecho que la FDA haya incluido una interacción particular con un fármaco no significa que abogue por el uso de un test genético antes de prescribir el fármaco correspondiente. Esto solo es necesario en el caso de que el test esté indicado para el diagnóstico, es decir, que sea esencial para el uso seguro y efectivo de un producto terapéutico, incluyendo los que identifican a los pacientes en los que este producto está contraindicado. Esta tabla publicada por la FDA, no pretende tener un efecto sobre las políticas y requerimientos regulatorios actuales, ni evaluar el uso efectivo y seguro de los tests para detectar variantes en los genes referenciados. Tampoco pretende dar una información exhaustiva de las interacciones descritas entre los fármacos y los genes.
Para algunas asociaciones farmacogenéticas se presenta una información específica sobre el manejo de los fármacos, pero en la mayoría de los casos no se ha evaluado el impacto de realizar los tests genéticos sobre el desenlace la enfermedad. Además, en el caso de existir estudios clínicos, en ellos solo se ha relacionado la variación genética con la farmacocinética del producto, y seguramente se desconocen las diferencias en la eficacia y seguridad entre los diferentes subgrupos genotípicos. Si no se mencionan la relación con la eficacia o la seguridad es porque no hay suficiente evidencia científica.
La FDA reconoce que los sanitarios tienen que tener en cuenta muchas pruebas científicas a la hora de prescribir un tratamiento. La información genética del paciente es solo uno de los muchos factores que puede afectar a las concentraciones y a la respuesta a un fármaco. Hay que saber que la siguiente tabla se limita solo a ciertas asociaciones farmacogenéticas y no contiene información exhaustiva sobre el uso efectivo y seguro de los fármacos. Los sanitarios se tienen que ceñir a la información aprobada por las agencias reguladoras. Además, esta tabla está dirigida a los médicos, y los pacientes no deben ajustar sus medicaciones sin consultar a su doctor.
Esta versión de la tabla se limita a las asociaciones farmacogenéticas de las variantes de los genes relacionados con las enzimas metabolizadoras de fármacos y los transportadores de fármacos, además de las variantes relacionadas con la predisposición a ciertos efectos secundarios. La FDA reconoce que existen otras asociaciones farmacogenéticas que hasta el momento no están listadas, por ello su objetivo es actualizar esta tabla con nueva información avalada por las pruebas científicas.
La tabla describe las interacciones gen-fármaco e indica el subgrupo específico al que se aplica la interacción. Los subgrupos afectados pueden ser portadores de una variante genética específica o de un genotipo inferido de un fenotipo. También pueden ser metabolizadores ultrarrápidos, normales, intermedios y lentos o tener una función del transportador ultrarrápida, normal, intermedia o lenta. Los de función o metabolismo normal no tienen variantes genéticas con impacto en el metabolismo o en la función del transportador. En general los metabolizadores ultrarrápidos tienen dos o más copias de una variante que incrementa la función metabólica, los metabolizadores intermedios o con función del transportador reducida suelen tener una o dos copias de una variante genética que reduce la capacidad de metabolizar o transportar un fármaco, y los metabolizadores lentos o con función de transporte lento suelen tener dos copias de una variante genética que causa poca o nula capacidad de metabolizar o transportar un fármaco.
Asociaciones farmacogenéticas en las que los datos avalan las recomendaciones para el manejo terapéutico
| Drug | Gene | Affected Subgroups+ | Description of Gene-Drug Interaction |
| Abacavir | HLA-B | *57:01 allele positive | Results in higher adverse reaction risk (hypersensitivity reactions). Do not use abacavir in patients positive for HLA-B*57:01. |
| Amifampridine | NAT2 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk. Use lowest recommended starting dosage and monitor for adverse reactions. Refer to FDA labeling for specific dosing recommendations. |
| Amifampridine Phosphate | NAT2 | poor metabolizers | Results in higher systemic concentrations. Use lowest recommended starting dosage (15 mg/day) and monitor for adverse reactions. |
| Amphetamine | CYP2D6 | poor metabolizers | May affect systemic concentrations and adverse reaction risk. Consider lower starting dosage or use alternative agent. |
| Aripiprazole | CYP2D6 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations. |
| Aripiprazole Lauroxil | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations. |
| Atomoxetine | CYP2D6 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk. Adjust titration interval and increase dosage if tolerated. Refer to FDA labeling for specific dosing recommendations. |
| Azathioprine | TPMT and/or NUDT15 | intermediate or poor metabolizers | Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations. |
| Belinostat | UGT1A1 | *28/*28 (poor metabolizers) | May result in higher systemic concentrations and higher adverse reaction risk. Reduce starting dose to 750 mg/m2 in poor metabolizers. |
| Brexpiprazole | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations. |
| Brivaracetam | CYP2C19 | intermediate or poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk. Consider dosage reductions in poor metabolizers. |
| Capecitabine | DPYD | intermediate or poor metabolizers | Results in higher adverse reaction risk (severe, life-threatening, or fatal toxicities). No dosage has proven safe in poor metabolizers, and insufficient data are available to recommend a dosage in intermediate metabolizers. Withhold or discontinue in the presence of early-onset or unusually severe toxicity. |
| Carbamazepine | HLA-B | *15:02 allele positive | Results in higher adverse reaction risk (severe skin reactions). Avoid use unless potential benefits outweigh risks and consider risks of alternative therapies. Patients positive for HLA-B*15:02 may be at increased risk of severe skin reactions with other drugs that are associated with a risk of Stevens Johnson Syndrome/Toxic Epidermal necrolysis (SJS/TEN). Genotyping is not a substitute for clinical vigilance. |
| Celecoxib | CYP2C9 | poor metabolizers | Results in higher systemic concentrations. Reduce starting dose to half of the lowest recommended dose in poor metabolizers. Consider alternative therapy in patients with juvenile rheumatoid arthritis. |
| Citalopram | CYP2C19 | poor metabolizers | Results in higher systemic concentrations and adverse reaction risk (QT prolongation). The maximum recommended dose is 20 mg. |
| Clobazam | CYP2C19 | intermediate or poor metabolizers | Results in higher systemic active metabolite concentrations. Poor metabolism results in higher adverse reaction risk. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations. |
| Clopidogrel | CYP2C19 | intermediate or poor metabolizers | Results in lower systemic active metabolite concentrations, lower antiplatelet response, and may result in higher cardiovascular risk. Consider use of another platelet P2Y12 inhibitor. |
| Clozapine | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. Dosage reductions may be necessary. |
| Codeine | CYP2D6 | ultrarapid metabolizers | Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age. |
| Deutetrabenazine | CYP2D6 | poor metabolizers | Results in higher systemic concentrations and adverse reaction risk (QT prolongation). The maximum recommended dosage should not exceed 36 mg (maximum single dose of 18 mg). |
| Dronabinol | CYP2C9 | intermediate or poor metabolizers | May result in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions. |
| Eliglustat | CYP2D6 | ultrarapid, normal, intermediate, or poor metabolizers | Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations. |
| Erdafitinib | CYP2C9 | *3/*3 (poor metabolizers) | May result in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions. |
| Flibanserin | CYP2C19 | poor metabolizers | May result in higher systemic concentrations and higher adverse reaction risk. Monitor patients for adverse reactions. |
| Flurbiprofen | CYP2C9 | poor metabolizers | Results in higher systemic concentrations. Use a reduced dosage. |
| Fluorouracil | DPYD | intermediate or poor metabolizer | Results in higher adverse reaction risk (severe, life-threatening, or fatal toxicities). No dosage has proven safe in poor metabolizers and insufficient data are available to recommend a dosage in intermediate metabolizers. Withhold or discontinue in the presence of early-onset or unusually severe toxicity. |
| Gefitinib | CYP2D6 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions. |
| Iloperidone | CYP2D6 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk (QT prolongation). Reduce dosage by 50%. |
| Irinotecan | UGT1A1 | *28/*28 (poor metabolizers) | Results in higher systemic active metabolite concentrations and higher adverse reaction risk (severe neutropenia). Consider reducing the starting dosage by one level and modify the dosage based on individual patient tolerance. |
| Lofexidine | CYP2D6 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk. Monitor for orthostatic hypotension and bradycardia. |
| Meclizine | CYP2D6 | ultrarapid, intermediate, or poor metabolizers | May affect systemic concentrations. Monitor for adverse reactions and clinical effect. |
| Metoclopramide | CYP2D6 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk. The recommended dosage is lower. Refer to FDA labeling for specific dosing recommendations. |
| Mercaptopurine | TPMT and/or NUDT15 | intermediate or poor metabolizers | Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations. |
| Mivacurium | BCHE | intermediate or poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk (prolonged neuromuscular blockade). Avoid use in poor metabolizers. |
| Pantoprazole | CYP2C19 | poor metabolizers | Results in higher systemic concentrations. Consider dosage reduction in children who are poor metabolizers. No dosage adjustment is needed for adult patients who are poor metabolizers. |
| Pimozide | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. Dosages should not exceed 0.05 mg/kg in children or 4 mg/day in adults who are poor metabolizers and dosages should not be increased earlier than 14 days. |
| Piroxicam | CYP2C9 | intermediate or poor metabolizers | Results in higher systemic concentrations. Consider reducing dosage in poor metabolizers. |
| Propafenone | CYP2D6 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk (arrhythmia). Avoid use in poor metabolizers taking a CYP3A4 inhibitor. |
| Siponimod | CYP2C9 | intermediate or poor metabolizers | Results in higher systemic concentrations. Adjust dosage based on genotype. Do not use in patients with CYP2C9 *3/*3 genotype. Refer to FDA labeling for specific dosing recommendations. |
| Succinylcholine | BCHE | intermediate or poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk (prolonged neuromuscular blockade). Avoid use in poor metabolizers. May administer test dose to assess sensitivity and administer cautiously via slow infusion. |
| Tacrolimus | CYP3A5 | intermediate or normal metabolizers | Results in lower systemic concentrations and lower probability of achieving target concentrations. Measure drug concentrations and adjust dosage based on trough whole blood tacrolimus concentrations. |
| Tetrabenazine | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. The maximum recommended single dose is 25 mg and should not exceed 50 mg/day. |
| Thioguanine | TPMT and/or NUDT15 | intermediate or poor metabolizers | Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations. |
| Thioridazine | CYP2D6 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk (QT prolongation). Predicted effect based on experience with CYP2D6 inhibitors. Contraindicated in poor metabolizers. |
| Tramadol | CYP2D6 | Ultrarapid metabolizers3 | Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment. |
| Valbenazine | CYP2D6 | poor metabolizers | Results in higher systemic active metabolite concentrations and higher adverse reaction risk (QT prolongation). Dosage reductions may be necessary. |
| Venlafaxine | CYP2D6 | poor metabolizers | Alters systemic parent drug and metabolite concentrations. Consider dosage reductions. |
| Vortioxetine | CYP2D6 | poor metabolizers | Results in higher systemic concentrations. The maximum recommended dose is 10 mg. |
| Warfarin | CYP2C9 | intermediate or poor metabolizers | Alters systemic concentrations and dosage requirements. Select initial dosage, taking into account clinical and genetic factors. Monitor and adjust dosages based on INR. |
| Warfarin | CYP4F2 | V433M variant carriers | May affect dosage requirements. Monitor and adjust doses based on INR. |
| Warfarin | VKORC1 | -1639G>A variant carriers | Alters dosage requirements. Select initial dosage, taking into account clinical and genetic factors. Monitor and adjust dosages based on INR. |
Asociaciones farmacognéticas en las que los datos indican un potencial impacto en la seguridad o en la respuesta
| Drug | Gene | Affected Subgroups+ | Description of Gene-Drug Interaction |
| Allopurinol | HLA-B | *58:01 allele positive | Results in higher adverse reaction risk (severe skin reactions). |
| Carbamazepine | HLA-A | *31:01 allele positive | Results in higher adverse reaction risk (severe skin reactions). Consider risk and benefit of carbamazepine use in patients positive for HLA-A*31:01. Genotyping is not a substitute for clinical vigilance. |
| Carvedilol | CYP2D6 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk (dizziness). |
| Cevimeline | CYP2D6 | poor metabolizers | May result in higher adverse reaction risk. Use with caution. |
| Codeine | CYP2D6 | poor metabolizers | Results in lower systemic active metabolite concentrations and may result in reduced efficacy. |
| Efavirenz | CYP2B6 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk (QT prolongation). |
| Isoniazid | Nonspecific (NAT) | poor metabolizers | May result in higher systemic concentrations and adverse reaction risk. |
| Lapatinib | HLA-DRB1 | *07:01 allele positive | Results in higher adverse reaction risk (hepatotoxicity). Monitor liver function tests regardless of genotype. |
| Lapatinib | HLA-DQA1 | *02:01 allele positive | Results in higher adverse reaction risk (hepatotoxicity). Monitor liver function tests regardless of genotype. |
| Nilotinib | UGT1A1 | *28/*28 (poor metabolizers) | Results in higher adverse reaction risk (hyperbilirubinemia). |
| Oxcarbazepine | HLA-B | *15:02 allele positive | Results in higher adverse reaction risk (severe skin reactions). Patients positive for HLA-B*15:02 may be at increased risk of severe skin reactions with other drugs that are associated with a risk of Stevens Johnson Syndrome/Toxic Epidermal necrolysis (SJS/TEN). Genotyping is not a substitute for clinical vigilance. |
| Pazopanib | HLA-B | *57:01 allele positive | May result in higher adverse reaction risk (liver enzyme elevations). Monitor liver function tests regardless of genotype. |
| Pazopanib | UGT1A1 | *28/*28 (poor metabolizers) | Results in higher adverse reaction risk (hyperbilirubinemia). |
| Perphenazine | CYP2D6 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk. |
| Procainamide | Nonspecific (NAT) | poor metabolizers | Alters systemic parent drug and metabolite concentrations. May result in higher adverse reaction risk. |
| Simvastatin | SLCO1B1 | 521 TC or 521 CC (intermediate or poor function transporters) | Results in higher systemic concentrations and higher adverse reaction risk (myopathy). The risk of adverse reaction (myopathy) is higher for patients on 80 mg than for those on lower doses. |
| Sulfamethoxazole and Trimethoprim | Nonspecific (NAT) | poor metabolizers | May result in higher adverse reaction risk. |
| Sulfasalazine | Nonspecific (NAT) | poor metabolizers | Results in higher systemic metabolite concentrations and higher adverse reaction risk. |
| Tolterodine | CYP2D6 | poor metabolizers | Results in higher systemic concentrations and higher adverse reaction risk (QT prolongation). |
Asociaciones farmacogenéticas en las que los datos demuestran solo un potencial impacto en las propiedades farmacocinéticas
No se ha establecido el impacto de estas variantes genéticas o de los fenotipos inferidos a partir de ellas en la seguridad o respuesta del fármaco correspondiente.
| 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. |
| 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 | poor metabolizers | May result in higher 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. |
| 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. |
| Voriconazole | CYP2C19 | intermediate or poor metabolizers | Results in higher systemic concentrations. |
En algunos casos una variante genética específica puede afectar al metabolismo de varios fármacos de forma diferente. En los casos en que la asociación se limita a variantes genéticas específicas y no se aplica a todos los individuos con el genotipo inferido del fenotipo las variantes se especifican en la tabla.
