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Vitamin K Antagonists [VKA] are the most frequently used oral anticoagulants in clinical practice; however, many patients fail to achieve adequate anticoagulation control. We conducted a randomized, placebo controlled, double blind study of Vitamin K1 (200mcg per day, Swanson Vitamins) in a population with predominantly venous thromboembolism aimed at evaluating its effectiveness in improving anticoagulation control in unstable patients. This study also aimed to evaluate the impact that clinical variables, patient anticoagulation knowledge, and genetic polymorphisms in genes known to impact warfarin and Vitamin K metabolism [VKORC1, CYP4F2, CYP2C9] had on anticoagulation control and intervention effectiveness. A total of N=54 patients were enrolled in the study over 15 months [January 2009 to June 2010]. Change score analysis and multivariate linear regression modelling of anticoagulation control measures were performed. No statistically significant reduction was observed in the Vitamin K1 arm for percent time in therapeutic range; however, reduction was observed in standard deviation of INRs [Change Score Vitamin K = -0.259, p=0.0261; Regression Model 95% C.I Beta Vitamin K = 0.38 to -0.08] during the intervention period. Adjusting for treatment group allocation, independent predictors of increased INR standard deviation included: >5 alcoholic drinks per week [95% C.I Beta = 0.04 to 0.41], self-reported dosing errors [95% C.I Beta = 0.13 to 0.47], and missed INR appointments [95% C.I Beta = 0.002 to 0.05]

Warfarin is the most widely prescribed oral anticoagulant used for the long-term treatment and prevention of thromboembolic events. Its administration is challenging as it may result in bleeding-related deaths, inadequate anticoagulation and fetal teratogenesis, including fetal warfarin syndrome. A number of environmental and genetic factors contribute to interindividual warfarin dosage variability. The CYP2C9 and VKORC1 genes explain 40- 50% of this variability. The aim of this study was to determine the frequency of known and any new variants in these genes in the SA black population, and correlate these variants and a small subset of environmental factors to dosage variability and pregnancy outcomes. I sequenced the exons and intron/exon boundaries of the CYP2C9 and VKORC1 genes in 100 random black control and 113 patient samples that had at least one pregnancy on warfarin. I observed six previously described CYP2C9 variants, 27 novel CYP2C9 variants, and three previously described VKORC1 variants. 14 of these variants were observed at an allele frequency of 0.02. Of these 14, six appear to decrease (all of which are CYP2C9 variants) and four increase (2 CYP2C9 variants and two VKORC1 variants) warfarin dosage requirement. These 14 CYP2C9 and VKORC1 variants along with a small subset of environmental factors account for 45.3% of warfarin dosage variability in the SA population. I observed an increase in the number of poor pregnancy outcomes in patients on high doses of warfarin. These results allow us to predict the maintenance dose of warfarin in SA black patients better, thereby reducing the risk of adverse effects, and identify those at risk of having a poor pregnancy outcome.

Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction. Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available. Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway. The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.

Vitamin K Antagonists [VKA] are the most frequently used oral anticoagulants in clinical practice; however, many patients fail to achieve adequate anticoagulation control. We conducted a randomized, placebo controlled, double blind study of Vitamin K1 (200mcg per day, Swanson Vitamins) in a population with predominantly venous thromboembolism aimed at evaluating its effectiveness in improving anticoagulation control in unstable patients. This study also aimed to evaluate the impact that clinical variables, patient anticoagulation knowledge, and genetic polymorphisms in genes known to impact warfarin and Vitamin K metabolism [VKORC1, CYP4F2, CYP2C9] had on anticoagulation control and intervention effectiveness. A total of N=54 patients were enrolled in the study over 15 months [January 2009 to June 2010]. Change score analysis and multivariate linear regression modelling of anticoagulation control measures were performed. No statistically significant reduction was observed in the Vitamin K1 arm for percent time in therapeutic range; however, reduction was observed in standard deviation of INRs [Change Score Vitamin K = -0.259, p=0.0261; Regression Model 95% C.I Beta Vitamin K = 0.38 to -0.08] during the intervention period. Adjusting for treatment group allocation, independent predictors of increased INR standard deviation included: >5 alcoholic drinks per week [95% C.I Beta = 0.04 to 0.41], self-reported dosing errors [95% C.I Beta = 0.13 to 0.47], and missed INR appointments [95% C.I Beta = 0.002 to 0.05]

Vitamin K Antagonists [VKA] are the most frequently used oral anticoagulants in clinical practice; however, many patients fail to achieve adequate anticoagulation control. We conducted a randomized, placebo controlled, double blind study of Vitamin K1 (200mcg per day, Swanson Vitamins) in a population with predominantly venous thromboembolism aimed at evaluating its effectiveness in improving anticoagulation control in unstable patients. This study also aimed to evaluate the impact that clinical variables, patient anticoagulation knowledge, and genetic polymorphisms in genes known to impact warfarin and Vitamin K metabolism [VKORC1, CYP4F2, CYP2C9] had on anticoagulation control and intervention effectiveness. A total of N=54 patients were enrolled in the study over 15 months [January 2009 to June 2010]. Change score analysis and multivariate linear regression modelling of anticoagulation control measures were performed. No statistically significant reduction was observed in the Vitamin K1 arm for percent time in therapeutic range; however, reduction was observed in standard deviation of INRs [Change Score Vitamin K = -0.259, p=0.0261; Regression Model 95% C.I Beta Vitamin K = 0.38 to -0.08] during the intervention period. Adjusting for treatment group allocation, independent predictors of increased INR standard deviation included: >5 alcoholic drinks per week [95% C.I Beta = 0.04 to 0.41], self-reported dosing errors [95% C.I Beta = 0.13 to 0.47], and missed INR appointments [95% C.I Beta = 0.002 to 0.05]

A varfarina é o anticoagulante oral mais prescrito no mundo todo. Algoritmos farmacogenéticos têm sido desenvolvidos para estimar a dose de varfarina. Os principais objetivos deste estudo foram desenvolver um algoritmo farmacogenético estimador de dose de varfarina e comparar o algoritmo desenvolvido neste trabalho com algoritmos disponíveis na literatura. Para atingir os objetivos foram incluídos dois grupos de pacientes tratados com varfarina (primeira coorte, n = 832; e segunda coorte, n = 133). Foram realizadas as genotipagens dos polimorfismos CYP2C9*2, CYP2C9*3 e VKORC1 (c.G1639A). A derivação do algoritmo foi realizada utilizando os dados dos pacientes da primeira coorte com dose estável (n=368) e foi replicado utilizando os dados dos pacientes provenientes da segunda coorte (n=133). Como resultado o algoritmo desenvolvido neste trabalho alcançou um coeficiente de determinação de 40%, incluindo as variáveis: idade, sexo, peso, altura, raça autodeclarada, uso de amiodarona, uso de indutores enzimáticos, os genótipos na VKORC1 (c.G1639A) e os fenótipos de acordo com polimorfismos CYP2C9. Os dados sugerem que o nosso algoritmo desenvolvido é mais acurado do que o algoritmo IWPC (The International Warfarin Pharmacogenetics Consortium) quando a aplicação é focada em pacientes brasileiros. Os algoritmos farmacogenéticos estimadores de dose de varfarina desenvolvidos para uma população específica podem ser mais efetivos para a terapia com varfarina em comparação com o uso de algoritmos estimadores de dose atualmente disponíveis / Warfarin is the most prescribed oral anticoagulant in the world. Pharmacogenetic algorithms have been developed to estimate the dose of warfarin. The main aims of the present study were to develop a pharmacogenetic-based warfarin dosing algorithm and compare algorithm developed in this study with others algorithms available in the literature. We included two patient cohorts treated with warfarin (first cohort, n = 832; and second cohort, n = 133). Polymorphisms were genotyped in the CYP2C9 * 2, CYP2C9 * 3 and VKORC1 (c.G1639A). The derivation of the algorithm was performed using the data from the patients in the first cohort with a stable dose (n = 368) and was replicated using data from patients from the second cohort (n = 133). Our algorithm achieved a determination of coefficient of 40%, including variables: age, sex, weight, height, self-declared race, use of amiodarone, use of enzymatic inducers, genotypes in VKORC1 (c.G1639A) and phenotypes according to CYP2C9 polymorphisms. Our data suggest that the developed algorithm is more accurate than the IWPC algorithm when the application is focused on patients from the Brazilian population. Pharmacogenetics- based warfarin dosing algorithms developed for a specific population may lead to improved performance compared use dosing algorithms currently available

HINTERGRUND UND ZIELE: Es ist allgemein anerkannt, dass neben Umweltfaktoren auch erbliche Faktoren in hohem Maße für interindividuelle Unterschiede in der Wirkweise von Arzneimitteln ursächlich sind. Die Spannweite der Arzneimittelwirkung bei gleicher Dosis kann individuell von Therapieversagen bis hin zu toxischer Überdosierung reichen und ist dabei stark von Arzneimittel-metabolisierenden Enzymen und Transportern beeinflusst. Genetische Varianten können teilweise interindividuelle Unterschiede in der Aktivität dieser Enzyme und Transporter erklären. Es bleibt jedoch unbekannt, wie viel der Variation in der Aktivität durch Erblichkeit bedingt ist und nicht durch bereits bekannte genetische Varianten erklärt werden kann. Primäres Ziel der Studie war es, diesen unbekannten erblichen Anteil in der Variation der Aktivität der Enzyme CY2D6 und CYP2C9 sowie des Transporters OATP1B1 zu quantifizieren. METHODEN: Die Erblichkeit in der Variation der Aktivität von CY2D6, CYP2C9 und OATP1B1 wurde in 20 mono- und 9 dizygoten, gleichgeschlechtlichen Zwillingspaaren untersucht. Die Testsubstanzen Metoprolol (CYP2D6) und Torasemid (CYP2C9 und OATP1B1) wurden jedem Studienteilnehmer wiederholt verabreicht und die Fläche unter der Kurve bis unendlich (AUC0-inf) für jedes Medikament und seinen Metaboliten als Marker der Enzym- (CYP2D6, CYP2C9) und Transporter- (OATP1B1) Aktivitäten bestimmt. Erblichkeit wurde mithilfe von Formeln mit den Korrelationskoeffizienten der Geschwister in den Gruppen mono- und dizygote Zwillingspaare, durch eine Strukturgleichungsmodellierung und durch Vergleich der intra- und interindividuellen Variation berechnet. ERGEBNISSE: Es wurde ein hohe Erblichkeit in der Variation der Aktivität von CYP2D6, CYP2C9 und OATP1B1 berechnet. Für CYP2D6 lag die Erblichkeit bei 88,5% -100%, für CYP2C9 und OATP1B1 bei 81% - 100%. Die bekannten genetischen Varianten konnten lediglich einen geringen Anteil der Variation in der AUC0-inf in der Studienpopulation erklären (38,2% durch genetische Varianten in CYP2D6, 6,5% durch genetische Varianten in CYP2C9 und 20,4% durch genetische Varianten in OATP1B1). FAZIT: Die Berechnungen zeigen, dass Erblichkeit einen großen Einfluss auf die Variation in der Aktivität der Enzyme CYP2D6, CYP2C9 und den Transporter OATP1B1 hat. Bekannte genetische Varianten können hiervon nur einen Teil erklären. Weitere Untersuchungen zu genetischen Regulation der Wirkweise von Arzneimitteln erscheinen vielversprechend.

A varfarina é o anticoagulante oral mais prescrito no mundo todo. Algoritmos farmacogenéticos têm sido desenvolvidos para estimar a dose de varfarina. Os principais objetivos deste estudo foram desenvolver um algoritmo farmacogenético estimador de dose de varfarina e comparar o algoritmo desenvolvido neste trabalho com algoritmos disponíveis na literatura. Para atingir os objetivos foram incluídos dois grupos de pacientes tratados com varfarina (primeira coorte, n = 832; e segunda coorte, n = 133). Foram realizadas as genotipagens dos polimorfismos CYP2C9*2, CYP2C9*3 e VKORC1 (c.G1639A). A derivação do algoritmo foi realizada utilizando os dados dos pacientes da primeira coorte com dose estável (n=368) e foi replicado utilizando os dados dos pacientes provenientes da segunda coorte (n=133). Como resultado o algoritmo desenvolvido neste trabalho alcançou um coeficiente de determinação de 40%, incluindo as variáveis: idade, sexo, peso, altura, raça autodeclarada, uso de amiodarona, uso de indutores enzimáticos, os genótipos na VKORC1 (c.G1639A) e os fenótipos de acordo com polimorfismos CYP2C9. Os dados sugerem que o nosso algoritmo desenvolvido é mais acurado do que o algoritmo IWPC (The International Warfarin Pharmacogenetics Consortium) quando a aplicação é focada em pacientes brasileiros. Os algoritmos farmacogenéticos estimadores de dose de varfarina desenvolvidos para uma população específica podem ser mais efetivos para a terapia com varfarina em comparação com o uso de algoritmos estimadores de dose atualmente disponíveis / Warfarin is the most prescribed oral anticoagulant in the world. Pharmacogenetic algorithms have been developed to estimate the dose of warfarin. The main aims of the present study were to develop a pharmacogenetic-based warfarin dosing algorithm and compare algorithm developed in this study with others algorithms available in the literature. We included two patient cohorts treated with warfarin (first cohort, n = 832; and second cohort, n = 133). Polymorphisms were genotyped in the CYP2C9 * 2, CYP2C9 * 3 and VKORC1 (c.G1639A). The derivation of the algorithm was performed using the data from the patients in the first cohort with a stable dose (n = 368) and was replicated using data from patients from the second cohort (n = 133). Our algorithm achieved a determination of coefficient of 40%, including variables: age, sex, weight, height, self-declared race, use of amiodarone, use of enzymatic inducers, genotypes in VKORC1 (c.G1639A) and phenotypes according to CYP2C9 polymorphisms. Our data suggest that the developed algorithm is more accurate than the IWPC algorithm when the application is focused on patients from the Brazilian population. Pharmacogenetics- based warfarin dosing algorithms developed for a specific population may lead to improved performance compared use dosing algorithms currently available

Orientador: Roberta Okamoto / Resumo: Atualmente, com os avanços da Farmacogenética, estudos estão demonstrando que a resposta individual de medicamentos pode ser diretamente afetada pela alteração da farmacocinética induzida pela genética de cada paciente, e isto pode induzir à ausência, redução, alteração ou aumento da atividade enzimática associada. Esse fato pode modificar a eficácia clínica de determinados medicamentos e, nos casos de anti-inflamatórios não esteroidais (AINEs), alterar sua capacidade de lidar com a dor e até aumentar a frequência e a gravidade dos efeitos adversos. Este estudo teve como objetivo genotipar e fenotipar o gene CYP2C9 em 89 pacientes saudáveis submetidos à cirurgia de terceiro molar inferior, sob medicação de 20 mg de tenoxicam por dia durante 4 dias, comparando a influência do gene na dor pós-operatória, edema, trismo, quantidade de medicamentos de socorro consumidos pelos pacientes, avaliação global e satisfação do paciente em relação à ingestão do medicamento. Trata-se de um ensaio clínico randomizado, desenvolvido no Departamento de Cirurgia e Traumatologia Bucomaxilofacial da Faculdade de Odontologia de Araçatuba (FOA/UNESP) e na Disciplina de Farmacologia do Departamento Ciências Biológicas da Faculdade de Odontologia de Bauru (FOB/USP). Foi realizado o sequenciamento genético dos participantes do estudo, a fim de verificar polimorfismos do gene CYP2C9, e estes dados foram cruzados com as características pós-operatórias acima mencionadas. Oitenta e nove participantes foram... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor