Pharmacogenetics of siponimod: A systematic review

Multiple sclerosis is a chronic inflammatory neurological disease, and siponimod (Mayzent) is the first oral treatment option for adult patients with secondary progressive multiple sclerosis. We performed a systematic review of the pharmacogenetics of Siponimod, and we found that (430 C>T; rs1799853) and CYP2C9 * 3 (1075 A>C; rs1057910), both translated no-function alleles, have been related to a lower metabolism of siponimod by CYP2C9 enzyme. The FDA-approved drug label and EMA risk management plan for siponimod require testing patients for CYP2C9 genotype before treatment starts. The FDA drug label states that siponimod is contraindicated in patients carrying a CYP2C9 * 3/* 3 genotype, and a daily maintenance dose of 1 mg in patients with CYP2C9 * 1/* 3 and * 2/* 3 genotypes. The EMA reported the potential long-term safety implications in CYP2C9 poor metabolizer patients treated with this drug. Based on this systematic review we concluded that CYP2C9 SNPs influence on siponimod response might be stated by assessing not only CYP2C9 * 2 and CYP2C9 * 3 but other genetic variants resulting in CYP2C9 IM/PM status. CYP2C9 IM phenotype translated from the CYP2C9 * 2 genotype should be revised since it is contradictory compared to other CYP2C9 no-function alleles, and CYP2C9 * 2 might be excluded from PGx testing recommendation before treatment starts with siponimod since it is not translated into a therapeutic recommendation

Azathioprine dose tailoring based on pharmacogenetic information: Insights of clinical implementation

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.biopha.2023.115706Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity

Genetic Polymorphisms in VEGFR Coding Genes (FLT1/KDR) on Ranibizumab Response in High Myopia and Choroidal Neovascularization Patients

A severe form of myopia defined as pathologic/high myopia is the main cause of visual impairment and one of the most frequent causes of blindness worldwide. It is characterized by at least 6 diopters or axial length (AL) of eyeball > 26 mm and choroidal neovascularization (CNV) in 5 to 10% of cases. Ranibizumab is a humanized recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor A (VEGF-A) used in the treatment of CNV. It acts by preventing VEGF-A from interacting with its receptors (VEGFR-1 and -2) encoded by the FLT1 and KDR genes. Several studies found that the KDR and FLT1 genotypes may represent predictive determinants of efficacy in ranibizumab-treated neovascular age-related macular degeneration (nAMD) patients. We performed a retrospective study to evaluate the association of single nucleotide polymorphisms (SNPs) in VEGFR coding genes with the response rate to ranibizumab in patients with high myopia and CNV. In the association study of genotypes in FLT1 with the response to ranibizumab, we found a significant association between two FLT1 variants (rs9582036, rs7993418) with ranibizumab efficacy at the 12-month follow-up. About the KDR gene, we found that two KDR variants (rs2305948, rs2071559) are associated with best-corrected visual acuity (BCVA) improvement and KDR (rs2239702) is associated with lower rates of BCVA worsening considering a 12-month follow-up period

Pharmacogenetic polymorphisms affecting bisoprolol response

This article is part of the thesis: Analysis of genetic variants associated with response to bisoprolol in patients with acute coronary syndrome with percutaneous coronary intervention with stent, within the doctoral program in Pharmacy at the University of Granada, to whom we thank for their collaboration. We would like to thank Dr. T. Eschenhagen and Dr. K. Kontula for sharing with us detailed information from their articles [16,22] which have allowed us to perform the meta-analysis.β-blockers are commonly prescribed to treat multiple cardiovascular (CV) diseases, but, frequently, adverse drug reactions and intolerance limit their use in clinical practice. Interindividual variability in response to β-blockers may be explained by genetic differences. In fact, pharmacogenetic interactions for some of these drugs have been widely studied, such as metoprolol. But studies that explore genetic variants affecting bisoprolol response are inconclusive, limited or confusing because of mixed results with other β-Blockers, different genetic polymorphisms observed, endpoint studied etc. Because of this, we performed a systematic review in order to find relevant genetic variants affecting bisoprolol response. We have found genetic polymorphism in several genes, but most of the studies focused in ADRB variants. The ADRB1 Arg389Gly (rs1801253) was the most studied genetic polymorphism and it seems to influence the response to bisoprolol, although studies are inconclusive. Even, we performed a meta-analysis about its influence on systolic/diastolic blood pressure in patients treated with bisoprolol, but this did not show statistically significant results. In conclusion, many genetic polymorphisms have been assessed about their influence on patients´ response to bisoprolol and the ADRB1 Arg389Gly (rs1801253) seems the most relevant genetic polymorphism in this regard but results have not been confirmed with a meta-analysis. Our results support the need of further studies about the impact of genetic variants on bisoprolol response, considering different genetic polymorphisms and conducting single and multiple SNPs analysis, including other clinical parameters related to bisoprolol response in a multivariate study

A new pharmacogenetic algorithm to predict the most appropriate dosage of acenocoumarol for stable anticoagulation in a mixed Spanish population

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.There is a strong association between genetic polymorphisms and the acenocoumarol dosage requirements. Genotyping the polymorphisms involved in the pharmacokinetics and pharmacodynamics of acenocoumarol before starting anticoagulant therapy would result in a better quality of life and a more efficient use of healthcare resources. The objective of this study is to develop a new algorithm that includes clinical and genetic variables to predict the most appropriate acenocoumarol dosage for stable anticoagulation in a wide range of patients. We recruited 685 patients from 2 Spanish hospitals and 1 primary healthcare center. We randomly chose 80% of the patients (n = 556), considering an equitable distribution of genotypes to form the generation cohort. The remaining 20% (n = 129) formed the validation cohort. Multiple linear regression was used to generate the algorithm using the acenocoumarol stable dosage as the dependent variable and the clinical and genotypic variables as the independent variables. The variables included in the algorithm were age, weight, amiodarone use, enzyme inducer status, international normalized ratio target range and the presence of CYP2C9∗2 (rs1799853), CYP2C9∗3 (rs1057910), VKORC1 (rs9923231) and CYP4F2 (rs2108622). The coefficient of determination (R2) explained by the algorithm was 52.8% in the generation cohort and 64% in the validation cohort. The following R2 values were evaluated by pathology: atrial fibrillation, 57.4%; valve replacement, 56.3%; and venous thromboembolic disease, 51.5%. When the patients were classified into 3 dosage groups according to the stable dosage (<11 mg/week, 11-21 mg/week, >21 mg/week), the percentage of correctly classified patients was higher in the intermediate group, whereas differences between pharmacogenetic and clinical algorithms increased in the extreme dosage groups. Our algorithm could improve acenocoumarol dosage selection for patients who will begin treatment with this drug, especially in extreme-dosage patients. The predictability of the pharmacogenetic algorithm did not vary significantly between diseases.This study was funded by a grant from the Spanish Ministry of Health and Social Policy (Instituto de Salud Carlos III, PI07/0710) and the Andalusian Regional Ministry of Health (Progress and Health Foundation, PI-0717-2013

Polimorfismos cyp2c19 y abcb1 en el tratamiento antiagregante con clopidogrel en pacientes con enfermedad arterial periférica sometidos a angioplastia transluminal percutánea, ictus o accidente isquémico transitorio

El clopidogrel es un profármaco cuyo metabolito activo ha demostrado su eficacia como antiagregante en la prevención de eventos cardiovasculares mayores secundarios a síndrome coronario agudo, enfermedad arterial periférica y cerebrovascular. Para la obtención del metabolito activo, clopidogrel se metaboliza a nivel hepático principalmente por la enzima CYP2C19, y su absorción depende en parte de la glicoproteina-P, cuya expresión está codificada por el gen ABCB1. La presencia de los polimorfismos CYP2C19*2, *3, *17 y ABCB1 C3435T en pacientes con síndrome coronario agudo sometidos a una intervención coronaria percutánea, ha sido asociada a una respuesta antiagregante variable en el tratamiento con clopidogrel. En pacientes con enfermedad arterial periférica o enfermedad cerebrovascular, en los que clopidogrel ha demostrado también su eficacia, la evidencia científica es menor. - Objetivo: Estudiar la influencia de los polimorfismos CYP2C19*2, *3, *17 y ABCB1 3435C>T sobre la respuesta a clopidogrel en pacientes con enfermedad arterial periférica y en pacientes con enfermedad cerebrovascular. - Metodología: Se realizaron 2 estudios: uno con pacientes con enfermedad arterial periférica de miembros inferiores sometidos a una angioplastia transluminal percutánea, y otro con pacientes diagnosticados de ictus o accidente isquémico transitorio. En ambos, los pacientes fueron tratados con clopidogrel desde la cirugía y desde el diagnóstico respectivamente. Se genotipó la presencia de los polimorfismos CYP2C19*2, *3, *17 y ABCB1 C3435T en los pacientes reclutados y se estudió su asociación con la eficacia del clopidogrel. Como variables respuesta (eficacia), en pacientes con enfermedad arterial periférica sometidos a angioplastia transluminal percutánea se estudió la ocurrencia de eventos isquémicos en el miembro intervenido durante el tratamiento con clopidogrel en 12 meses de seguimiento, y en los pacientes con ictus o accidente isquémico transitorio se estudió como evento primario la ocurrencia de infarto agudo de miocardio, ictus o muerte cardiovascular desde el diagnóstico, durante el tiempo de tratamiento con clopidogrel, hasta el 31 de julio de 2017. - Resultados: En pacientes con enfermedad arterial periférica y angioplastia transluminal percutánea tratados con clopidogrel, la presencia del polimorfismo CYP2C19*2 se asoció de manera independiente (OR=4.89; IC 95%=1.32-12.83; p=0.018) y combinado con el genotipo ABCB1 3435TT (OR=4.66; IC 95%=1.37-15.84; p=0.014), con un aumento del riesgo de sufrir un evento isquémico en el miembro intervenido. Además, en estos pacientes, se asoció la presencia de estos polimorfismos con la mala evolución de la clasificación de Fontaine, ondas pletismográficas y distancia de claudicación. En pacientes con ictus o accidente isquémico transitorio tratados con clopidogrel, la presencia del CYP2C19*2 mostró una asociación estadísticamente significativa con el aumento del riesgo de la combinada de ictus o accidente isquémico transitorio, infarto agudo de miocardio y muerte cardiovascular (evento primario) (OR=5.07; IC95%=1.2-21.45; p=0.023). Por otro lado, en estos pacientes, se asoció la presencia del CYP2C19*17 con la protección frente la aparición del evento primario (OR=0.19; IC95%=0.03-1.09; p=0.037). - Conclusiones: Los polimorfismos CYP2C19*2 y ABCB1 3435C>T pueden ser marcadores genéticos de la aparición de eventos isquémicos en pacientes andaluces con enfermedad arterial periférica y sometidos a angioplastia transluminal percutánea tratados con clopidogrel. El polimorfismo CYP2C19*2 puede ser un marcador de la aparición de eventos cardiovasculares mayores en pacientes con ictus o accidente isquémico transitorio tratados con clopidogrel, mientras, el CYP2C19*17 puede ser indicador de la prevención frente la aparición de estos eventos entre estos pacientes.Tesis Univ. Granada. Programa Oficial de Doctorado en Farmaci

Genetic Polymorphisms Affecting Ranibizumab Response in High Myopia Patients

This article includes results from a doctoral thesis being developed linked to the doctoral program in Pharmacy at the University of Granada, to whom we thank for their collaboration. We also would like to thank patients for their consent and collaboration in the study; nurses and personnel of the ophthalmology unit in the “Hospital San Cecilio” (Granada) for their kindly collaboration in the recruitment of patients; and personnel of the Genomics Unit in the Pfizer—University of Granada—Junta de Andalucía Centre for Genomics and Oncological Research (GENYO) for their excellent technical assistance.High myopia is an ophthalmic pathology that affects half of the young adults in the United States and Europe and it is predicted that a third of the world's population could be nearsighted at the end of this decade. It is characterized by at least 6 diopters or axial length > 26 mm and, choroidal neovascularization (CNV) in 5 to 11% of cases. Ranibizumab is a recombinant humanized monoclonal antibody fragment. It is an anti-vascular endothelial growth factor (anti-VEGF) drug used in the treatment of CNV. Many genetic polymorphisms have been associated with interindividual differences in the response to ranibizumab, but these associations were not yet assessed among patients with high myopia and CNV. We performed a retrospective study assessing the association of genetic polymorphisms with response to ranibizumab in patients with CNV secondary to high myopia (mCNV). We included genetic polymorphisms previously associated with the response to drugs used in CNV patients (bevacizumab, ranibizumab, aflibercept, and photodynamic therapy (PDT)). We also included genetic variants in the VEGFA gene. Based on our results, ARMS2 (rs10490924) and CFH (rs1061170) are associated with response to ranibizumab in high myopia patients; and, included VEGFA genetic polymorphisms are not associated with ranibizumab response in our population but might be related to a higher risk of CNV

Pharmacogenetics in the Treatment of Cardiovascular Diseases and Its Current Progress Regarding Implementation in the Clinical Routine.

There is a special interest in the implementation of pharmacogenetics in clinical practice, although there are some barriers that are preventing this integration. A large part of these pharmacogenetic tests are focused on drugs used in oncology and psychiatry fields and for antiviral drugs. However, the scientific evidence is also high for other drugs used in other medical areas, for example, in cardiology. In this article, we discuss the evidence and guidelines currently available on pharmacogenetics for clopidogrel, warfarin, acenocoumarol, and simvastatin and its implementation in daily clinical practice

The study protocol for a non-randomized controlled clinical trial using a genotype-guided strategy in a dataset of patients who undergone percutaneous coronary intervention with stent

This article contains data related to the research article entitled “Results of genotype–guided antiplatelet therapy in patients undergone percutaneous coronary intervention with stent” (J. Sánchez-Ramos, C.L. Dávila-Fajardo, P. Toledo Frías, X. Díaz Villamarín, L.J. Martínez-González, S. Martínez Huertas, F. Burillo Gómez, J. Caballero Borrego, A. Bautista Pavés, M.C. Marín Guzmán, J.A. Ramirez Hernández, C. Correa Vilches, J. Cabeza Barrera, 2016) (1). This data article reports, for the first time, about the non-randomized clinical trial protocol that check if CYP2C19/ABCB1 genotype–guided strategy in which the choice of antiplatelet therapy is based on the genetic test, reduces the rates of cardiovascular events and bleeding compared to a non-tailored strategy in patients undergone percutaneous coronary intervention (PCI) with stent. The data included in this article are: design and setting of the study, study population, inclusion and exclusion criteria, definition of the intervention, objectives, variables (baseline characteristics and during the follow-up), study procedures, collection and treatment of the biological sample, genotyping, withdrawal criteria, sample size, statistic analysis, ethical aspects, information sheet and consent form. The authors confirm that this study has been registered in Eudra CT (Eudra CT: 2016-001294-33).Ministry of Health of Government of Andalusia PI-057/201