RESUMEN
Aim: This study evaluated associations between CYP3A4*22 and variants in other pharmacogenes (CYP3A5, SULT2A1, ABCB1, ABCG2, ERCC1) and the risk for palbociclib-associated toxicities.Materials & methods: Two hundred cancer patients who received standard-of-care palbociclib were genotyped and associations with toxicity were evaluated retrospectively.Results: No significant associations were found for CYP3A4*22, CYP3A5*3, ABCB1_rs1045642, ABCG2_rs2231142, ERCC1_rs3212986 and ERCC1_rs11615. Homozygous variant carriers of SULT2A1_rs182420 had higher incidence of dose modifications due to palbociclib toxicity (odds ratio [OR]: 4.334, 95% CI: 1.057-17.767, p = 0.042). ABCG2_rs2231137 variant carriers had borderline higher incidence of grade 3-4 neutropenia (OR: 4.14, 95% CI: 0.99-17.37, p = 0.052).Conclusion: Once validated, SULT2A1 and ABCG2 variants may be useful to individualize palbociclib dosing to minimize toxicities and improve treatment outcomes.
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Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Alelos , Proteínas de Neoplasias , Piperazinas , Piridinas , Humanos , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Masculino , Femenino , Piridinas/efectos adversos , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Anciano , Adulto , Estudios Retrospectivos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Genotipo , Arilsulfotransferasa/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Aim: The pharmacokinetics and pharmacodynamics of vemurafenib are characterized by a wide interpatient variability. Since multiple polymorphic enzymes and drug transporters are involved in vemurafenib pharmacokinetics, we studied associations of polymorphisms on vemurafenib-associated toxicities. Patients & methods: Prospectively collected samples of 97 melanoma patients treated with vemurafenib alone (n = 62) or in combination with cobimetinib (n = 35) were genotyped for ABCB1 (3435C>T), ABCG2 (421C>A, 34G>A) and CYP3A4 (*22, 15389C>T) polymorphisms. Associations between these variants and the incidence of toxicities were studied. Results:CYP3A4*22 was significantly associated with increased risk for grade ≥3 nausea, grade 1-4 hyperbilirubinemia, and cutaneous squamous cell carcinoma. ABCB1 3435C>T was a predictor for grade ≥3 toxicity. Conclusion: Genetic variants in CYP3A4 and ABCB1 are associated with vemurafenib-associated toxicities.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Citocromo P-450 CYP3A/genética , Melanoma/tratamiento farmacológico , Proteínas de Neoplasias/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Azetidinas/administración & dosificación , Azetidinas/efectos adversos , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Melanoma/genética , Melanoma/patología , Persona de Mediana Edad , Variantes Farmacogenómicas/genética , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Polimorfismo de Nucleótido Simple/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Vemurafenib/administración & dosificación , Vemurafenib/efectos adversosRESUMEN
The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping.