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

最大后验贝叶斯估算法制定华法林个体化给药案例探讨

目的:探讨临床药师在华法林个体化给药方案制定及实施监护过程中发挥的作用。方法:临床药师采用最大后验贝叶斯估算法制定华法林患者的给药方案,并对方案实施过程进行了监护,及时识别了药物相互作用导致的INR升高,避免了出血不良反应的发生,同时也及时发现了患者漏服药物导致的国际标准化比值(INR)降低,避免了患者再次发生血栓。结果:最大后验贝叶斯估算法可以较好地估算和指导临床用药,对于个体化给药方案具有极大的参考价值。结论:根据基因检测结果选择合适的算法为华法林患者制定了个体化给药方案后,临床药师还需要对整个给药方案实施过程提供全程化的监护,以便及时发现疾病、药物相互作用、依从性不佳等导致的INR异常波动,从而提供抗凝效果,减少出血和栓塞等不良反应。福建省科技计划引导性项目(编号:2015Y0020

Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals

The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene—gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients’ data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7–10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived

Individualización del tratamiento con acenocumarol: desarrollo de nuevos algoritmos farmacogenéticos y su validación en enfermedad tromboembólica venosa

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Cirugía. Fecha de lectura: 24-01-202

Pharmacogenetic studies with oral anticoagulants. Genome-wide association studies in vitamin K antagonist and direct oral anticoagulants

Altres ajuts: This work was supported by Boeringher Ingelheim funding (SEDMAN Project).Oral anticoagulants (OAs) are the recommended drugs to prevent cardiovascular events and recurrence in patients with atrial fibrillation (AF) and cardioembolic stroke. We conducted a literature search to review the current state of OAs pharmacogenomics, focusing on Genome Wide Association Studies (GWAs) in patients treated with vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). VKAs: Warfarin, acenocoumarol, fluindione and phenprocoumon have long been used, but their interindividual variability and narrow therapeutic/safety ratio makes their dosage difficult. GWAs have been useful in finding genetic variants associated with VKAs response. The main genes involved in VKAs pharmacogenetics are: VKORC1, CYP2C19 and CYP4F2. Variants in these genes have been included in pharmacogenetic algorithms to predict the VKAs dose individually in each patient depending on their genotype and clinical variables. DOACs: Dabigatran, apixaban, rivaroxaban and edoxaban have been approved for patients with AF. They have stable pharmacokinetics and do not require routine blood checks, thus avoiding most of the drawbacks of VKAs. Except for a GWAs performed in patients treated with dabigatran, there is no Genome Wide pharmacogenomics data for DOACs. Pharmacogenomics could be useful to predict the better clinical response and avoid adverse events in patients treated with anticoagulants, identifying the most appropriate anticoagulant drug for each patient. Current pharmacogenomics data show that the polymorphisms affecting VKAs or DOACs are different, concluding that personalized medicine based on pharmacogenomics could be possible. However, more studies are required to implement personalized medicine in clinical practice with OA and based on pharmacogenetics of DOACs

Acenocoumarol Pharmacogenetic Dosing Algorithm versus Usual Care in Patients with Venous Thromboembolism: A Randomised Clinical Trial

Patients with venous thromboembolism (VTE) require immediate treatment with anticoagulants such as acenocoumarol. This multicentre randomised clinical trial evaluated the effectiveness of a dosing pharmacogenetic algorithm versus a standard-of-care dose adjustment at the beginning of acenocoumarol treatment. We included 144 patients with VTE. On the day of recruitment, a blood sample was obtained for genotyping (CYP2C9*2, CYP2C9*3, VKORC1, CYP4F2, APOE). Dose adjustment was performed on day 3 or 4 after the start of treatment according to the assigned group and the follow-up was at 12 weeks. The principal variable was the percentage of patients with an international normalised ratio (INR) within the therapeutic range on day 7. Thirty-four (47.2%) patients had an INR within the therapeutic range at day 7 after the start of treatment in the genotype-guided group compared with 14 (21.9%) in the control group (p = 0.0023). There were no significant differences in the time to achieve a stable INR, the number of INRs within the range in the first 6 weeks and at the end of study. Our results suggest the use of a pharmacogenetic algorithm for patients with VTE could be useful in achieving target INR control in the first days of treatment

Impact of gamma-glutamyl carboxylase gene polymorphisms on warfarin dose requirement: A systematic review and meta-analysis

AbstractBackgroundThe Gamma-glutamyl carboxylase (GGCX) gene, as with Vitamin K Epoxide Reductase Complex Subunit 1(VKORC1), CytochromeP450 Complex Subunit 14 F2 (CYP4F2) and CytochromeP450 Complex Subunit2C9 (CYP2C9), is a candidate predictor for appropriate maintenance warfarin dose. However, the association between GGCX gene polymorphisms and warfarin dose requirement is still controversial. To quantify the influence of GGCX polymorphisms on warfarin dose requirements, we performed a systematic review and meta-analysis.MethodsAccording to PRISRM statement (Preferred reporting items for systematic reviews and meta-analyses), a comprehensive literature search was undertaken through August 2014 looking for eligible studies in Embase, Pubmed,Web of Science and the Cochrane Library. The impact of GGCX polymorphisms on mean daily warfarin dose (MDWD) was counted by means of Z test. RevMan 5.2.7 software (developed by the Cochrane Collaboration) was applied to analyze the relationship between GGCX gene polymorphisms and warfarin dose requirements.ResultsNineteen articles including 21 studies with a total of 6957 patients were included in the meta-analysis. Among three investigated single nucleotide polymorphisms (SNPs), rs11676382 showed higher CC genotype frequencies in Asian than those in Caucasian(97.7% vs. 86.9%); patients who were “G carriers” (that is, carried the GGCX rs11676382 CG or GG genotypes) required 27% lower warfarin dose than CC genotype[95%Confidence Interval(CI)=17%-37%, P=0.000, I2%=82.0 and PQ=0.000], moreover, stratified analysis by ethnicity showed similar results in Caucasian(23% lower, 95%CI=12%-33%), but not in Asian. With respect to genetic variation of rs699664 and rs121714145 SNPs, no significant impact on warfarin dose requirements were demonstrated.ConclusionsThis meta-analysis suggested that GGCX rs11676382 polymorphism may be one of factors affecting the dose of warfarin requirement, and the effects are different in different ethnicities. Further studies about this topic in different ethnicities with larger samples are expected to be conducted to validate our results

Warfarin Pharmacogenomics in a Hispanic Population: A Candidate SNP Study

Background: Warfarin remains one of the most widely prescribed anticoagulants but is also a leading cause of adverse drug reactions. Genotype-guided warfarin dosing algorithms enable accurate dose estimation, potentially leading to improved safety and efficacy. However, genotype-guided dosing algorithms were developed primarily in populations of European descent and limited data are available regarding single nucleotide polymorphisms (SNPs) that significantly influence warfarin dose in Hispanic populations. Research Aim: The objective of this study was to determine whether clinical factors and SNPs previously associated with stable warfarin dose variability in populations of European and Hispanic descent accurately predicted warfarin stable dose in a Hispanic population. Study Design: Self-reported Hispanic and Latino patients on stable warfarin dose (defined as the same dose for at least two clinic visits separated by at least two weeks) were recruited. Methods: Candidate SNPs, including CYP2C9*2/*3, VKORC1-1639G>A, CYP4F2*3, and NQO1*2, were genotyped and clinical data were collected using a survey and the electronic medical record. Stepwise linear regression was performed to determine variables that significantly predicted square root of weekly warfarin dose. Results: A total of 76 patients of primarily Mexican American ancestry participated. All SNPs were within Hardy-Weinberg Equilibrium. The final stepwise regression model incorporated six variables, which explained 71% of the variability in warfarin weekly dose requirements. Significant predictors included weight (R2=0.287, p<0.0001), age (R2=0.143, p<0.0001), amiodarone use (R2=0.067, p=0.0005), and prior stroke (R2=0.025, p=0.02). Significant SNPs included VKORC1-1639A (R2=0.152, p<0.0001), and CYP2C9*2/*3 (R2=0.032, p=0.02). CYP4F2*3 and NQO1*2 did not significantly impact warfarin dose requirements despite previously published associations in Hispanic populations. Conclusion: These findings suggest that clinical and genetic predictors of warfarin weekly dose requirements are similar among populations of European descent and Hispanic populations with Mexican American ancestry. These results require replication and validation in independent cohorts with similar ethnicity, but advance our understanding of influences on warfarin dose variability among different race/ethnic groups

La farmacogenética como herramienta de la medicina personalizada: desarrollo de estrategias para su implementación en la práctica clínica e identificación de nuevas asociaciones

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 28-03-2019La Farmacogenética (PGx) representa en la actualidad una de las herramientas más importantes del paradigma de la medicina personalizada permitiendo evitar Reacciones Adversas a Medicamentos (RAM) así como maximizar la eficacia de los tratamientos farmacológicos y, en definitiva, optimizar el proceso de selección de la mejor pauta terapéutica para cada paciente. El primer objetivo de esta tesis doctoral, fue el desarrollo de una estrategia para la implementación de la PGx en la rutina clínica de un hospital de primer nivel asistencial adscrito al Sistema Nacional de Salud (SNS). Esta estrategia está basada en una plataforma de microarray de SNPs que permite el genotipado simultáneo de 180 polimorfismos de respuesta a fármacos. A lo largo de este período (2013-2018) se han realizado un total de 3532 estudios PGx para distintos fármacos y en pacientes de distintas patologías dentro de la rutina clínica del hospital. Por otro lado, se evaluó la utilidad de un protocolo multidisciplinar para la implementación del genotipado anticipado de CYP2C19 en una cohorte de pacientes hematológicos previo al trasplante de progenitores hematopoyéticos, definida como población de riesgo para el tratamiento o profilaxis con Voriconazol. Esta estrategia permitió aumentar notablemente el porcentaje de pacientes que alcanzaban el rango terapéutico diana así como reducir el tiempo necesario para alcanzarlo, mejorando de este modo el éxito del tratamiento. El último objetivo de este trabajo fue la identificación de nuevas asociaciones PGx que permitiesen mejorar los algoritmos monogénicos existentes para la optimización del tratamiento con Tacrolimus y Voriconazol, mediante la incorporación de nuevos biomarcadores asociados a la variabilidad en su farmacocinética. A lo largo de esta tesis doctoral se proponen nuevos biomarcadores no incluidos hasta la fecha en los algoritmos clínicos que podrían resultar de interés para la individualización del tratamiento con estos fármacos. En definitiva, en este trabajo se ha desarrollado una estrategia que ha permitido la implementación de la PGx en la práctica clínica de nuestro centro. Además, se ha demostrado la utilidad en la práctica clínica de un protocolo de genotipado anticipado en una cohorte de pacientes hematológicos previo al trasplante de progenitores hematopoyéticos definida como población de riesgo para el tratamiento o profilaxis con Voriconazol. Finalmente, se proponen modelos poligénicos de predicción del perfil farmacocinético de dos fármacos de uso clínico frecuente, Voriconazol y Tacrolimus, que parecen mejorar los algortimos clínicos monogénicos desarrollados hasta la fecha.Pharmacogenetics (PGx) constitutes an essential tool for personalized medicine. It minimizes Adverse Drug Reactions (RAM) and maximizes treatment efficacy; and ultimately optimizes treatment selection for each patient. The first goal of this doctoral thesis was the development of a strategy for the implementation of PGx in the clinical routine of a third-level care hospital of the Spanish National Health Service. This strategy was based on a SNP-array platform allowing simultaneous genotyping of 180 SNPs related to drug response. During this period (2013-2018) we have performed 3532 PGx tests for different drugs and diseases in the clinical routine of our center. We have also evaluated the utility of a multidisciplinary protocol for the implementation of preemptive genotyping of CYP2C19 in a cohort of haematological patients, defined as risk population for treatment or prophylaxis with Voriconazole. This strategy resulted in a significant increase in the percentage of patients achieving Voriconazole goal therapeutic range and reduced the time window required to achieve it, and therefore improved treatment success. The last aim of this work was the identification of new PGx associations that improved the existing monogenic algorithms for Tacrolimus and Voriconazole treatment optimization, by the incorporation of new biomarkers related to their PGx interindividual variability. During this doctoral thesis we propose new biomarkers, not previously included in clinical prediction algorithms that may be of interest for treatment individualization with these drugs in the clinical practice. In summary, we have developed a strategy that allowed the implementation of PGx in the clinical routine of our center. In addition, we have demonstrated the clinical utility of a preemptive genotyping protocol in a cohort of haematological patients before allogenic hematopoietic cell transplantation defined as a risk population for treatment or prophylaxis with Voriconazole. Finally, we here propose two polygenic predictive models of the pharmacokinetic profile of Tacrolimus and Voriconazole that seem to improve the existing monogenic predictive algorithms

The role of genetic polymorphisms in warfarin anticoagulant therapy

Oralni antikoagulans varfarin se već desetljećima koristi u terapiji i/ili prevenciji tromboembolijskih stanja različite etiologije. Varfarin ima uzak terapijski raspon i pokazuje veliku interindividualnu varijabilnost u odgovoru na terapiju, što može potencijalno rezultirati i po život opasnim komplikacijama uslijed prekomjernog antikoagulacijskog učinka i krvarenja. Cilj ovoga istraživanja bio je ispitati utjecaj polimorfizama VKORC1 -1639G>A, VKORC1 1173C>T, CYP2C9*2, CYP2C9*3, CYP4F2*3 i GGCX 12970C>G te kliničkih i okolišnih čimbenika na stabilnu dozu održavanja i nuspojave terapije varfarinom. U istraživanju su sudjelovala 204 bolesnika na terapiji varfarinom i 420 zdravih ispitanika. Rezultati genotipizacije na zdravim ispitanicima pokazuju kako je učestalost polimorfizama VKORC1 1639G>A i VKORC1 1173>T u populaciji Hrvatske u skladu s učestalošću u europskim populacijama. Rezultati istraživanja na skupini bolesnika na terapiji varfarinom ukazuju na statistički značajnu povezanost stabilne doze održavanja varfarina sa sljedećim čimbenicima: genotipovima CYP2C9, VKORC1 i CYP4F2, zatim s fizičkom aktivnošću, tjelesnom površinom, te uzimanjem lijekova koji utječu na metabolizam varfarina. Algoritam za predviđanje doze dobiven višestrukom linearnom regresijom u stanju je objasniti 49,8 % varijabilnosti doze varfarina. Dokazana je statistički značajna povezanost vremena potrebnog za postizanje stabilne doze varfarina s polimorfizmom CYP4F2*3 te povezanost udjela vremena provedenog unutar terapijskog raspona i pojave nuspojava terapije varfarinom u obliku prekomjerne antikoagulacije s polimorfizmima VKORC1 -1639G>A i/ili VKORC1 1173C>T. Isto tako, utvrđena je statistički značajna povezanost VKORC1 -1639G>A i/ili VKORC1 1173C>T te CYP4F2*3 s nuspojavama terapije varfarinom u obliku krvarenja.Warfarin is the most commonly used oral anticoagulant worldwide. It is used for over a half of century for prevention of thromboembolic disorders. Dosage of warfarin is difficult due to a very narrow therapeutic index (with lifethreatening overdose complications) and wide interindividual variability. Aim of this study was to investigate association of VKORC1 -1639G>A, VKORC1 1173C>T, CYP2C9*2, CYP2C9*3, CYP4F2*3 and GGCX 12970C>G genetic polymorphisms, along with some clinical and environmental factors, on warfarin maintenance dose and adverse effects of warfarin therapy. This study included 204 patients on warfarin therapy and 420 healthy volunteers. Results of genotyping study on healthy population confirms that allele frequencies for VKORC1 -1639G>A and VKORC1 1173C>T polymorphisms in Croatian population are in good agreement with other populations of European ancestry. Results obtained on warfarin patient population indicate that warfarin maintenance dose was significantly associated with following variables: CYP2C9, VKORC1 and CYP4F2 genotype, physical activity, body surface area and concomitant usage of drugs that influence warfarin metabolism. Dosage prediction algorithm obtained with multiple regression could explain 49,8 % of dose variability. Time to warfarin stable dose was significantly associated with CYP4F2*3 genetic polymorphism. Time in therapeutic range was significantly associated with VKORC1 -1639G>A and VKORC1 1173C>T polymorphisms. VKORC1 -1639G>A and VKORC1 1173C>T polymorphisms were also significantly associated with time to first overanticoagulation in warfarin therapy. VKORC1 -1639G>A, VKORC1 1173C>T and CYP4F2*3 polymorphisms were significantly associated with bleedings encountered during warfarin therapy