Contexte: Bien que plusieurs algorithmes pharmacogénétiques de prédiction de doses de warfarine aient été publiés, peu d’études ont comparé la validité de ces algorithmes en pratique clinique réelle. Objectif: Évaluer trois algorithmes pharmacogénomiques dans une population de patients qui initient un traitement à la warfarine et qui souffrent de fibrillation auriculaire ou de problèmes de valves cardiaques. Analyser la performance des algorithmes de Gage et al., de Michaud et al. ainsi que de l’IWPC quant à la prédiction de la dose de warfarine permettant d’atteindre l’INR thérapeutique. Méthodes: Un devis de cohorte rétrospectif fut utilisé afin d’évaluer la validité des algorithmes chez 605 patients ayant débuté une thérapie de warfarine à l’Institut de Cardiologie de Montréal. Le coefficient de corrélation de Pearson ainsi que l’erreur absolue moyenne ont été utilisés pour évaluer la précision des algorithmes. L’exactitude clinique des prédictions de doses fut évaluée en calculant le nombre de patients pour qui la dose prédite était sous-estimée, idéalement estimée ou surestimée. Enfin, la régression linéaire multiple a été utilisée pour évaluer la validité d’un modèle de prédiction de doses de warfarine obtenu en ajoutant de nouvelles covariables. Résultats : L’algorithme de Gage a obtenu la proportion de variation expliquée la plus élevée (R2 ajusté = 44 %) ainsi que la plus faible erreur absolue moyenne (MAE = 1.41 ± 0.06). De plus, la comparaison des proportions de patients ayant une dose prédite à moins de 20 % de la dose observée a confirmé que l’algorithme de Gage était également le plus performant. Conclusion : Le modèle publié par Gage en 2008 est l’algorithme pharmacogénétique le plus exact dans notre population pour prédire des doses thérapeutiques de warfarine. / Background: Although numerous genotype-based warfarin dosing algorithms have been published, there is little data comparing the predictive ability of these algorithms in real clinical practice. Objectives: Our goal was to evaluate the performance of pharmacogenetic algorithms in an unselected patient population initiating warfarin treatment for atrial fibrillation or valve disease in a real-world clinical setting. The principal objective of the analysis was to determine if Gage’s, Michaud’s, and IWPC algorithms could predict the dose achieving the therapeutic International normalized ratio (INR). Methods: Data from a retrospective cohort study of 605 patients initiating warfarin therapy at the Montreal Heart Institute was used. We compared the dose predicted by the algorithms to the dose achieving the therapeutic INR. Pearson’s correlation coefficient and mean absolute error (MAE) were used to evaluate the predictive accuracy of the algorithms. Clinical accuracy of the predictions was assessed by computing the proportion of patients in which the predicted dose was under-estimated, ideally estimated, or overestimated. Finally, we used multiple linear regression analysis to evaluate the accuracy of a predictive model obtained by adding additional covariables in predicting therapeutic warfarin doses. Results: The proportion of variation explained (adjusted R2) was the highest for Gage’s algorithm (R2 = 44 %) and the mean absolute error was the smallest for the predictions made by Gage’s algorithm (MAE = 1.41 ± 0.06). Moreover, when we compared the proportion of patients whose predicted doses are within ± 20 % of the observed stable dose, Gage’s algorithm also performed the best overall. Conclusion: The algorithm published by Gage et al. in 2008 is the most accurate pharmacogenetically based equation in predicting therapeutic warfarin dose in our study population.

The bioavailability of a drug can be described as the fraction of an orally administered dose that reaches the systemic circulation and is often limited by first-pass metabolism in the gut and the liver. It is important to have knowledge about these processes since the systemic blood drug concentration is tightly connected to the effect of the drug. The general aim of this project was to quantitatively examine the role of the intestine in relation to the liver in first-pass metabolism of orally administered drugs. The first-pass metabolism of verapamil and raloxifene was investigated in detail with in vivo, in vitro and simulation studies, using the pig as an experimental model. The intestine contributed to the same extent as the liver to first-pass metabolism of R/S-verapamil in vivo in pigs. The S-isomer of verapamil was found in lower plasma concentrations compared to the R-isomer after oral dosing. The in vitro metabolism of verapamil in pig and human liver showed interspecies similarity and indicated equal intrinsic clearance for R- and S-verapamil. Through physiologically based pharmacokinetic modeling the stereoselectivity was explained by a combination of several processes, including enantioselective plasma protein binding, blood-to-plasma partition, and gut and liver tissue distribution. For raloxifene the intestine was the dominating organ in first-pass glucuronidation in vivo in pigs. Furthermore, the raloxifene concentration entering the intestine or the dose administered in the gut did not influence the plasma PK of raloxifene and indicated that the intestinal metabolism was not saturable with clinical relevant doses. For both verapamil and raloxifene, a time-dependent hepatic metabolism was noted with major consequences to the pharmacokinetic of the drugs. This project has pointed out the importance of intestinal metabolism in the overall first-pass extraction of drugs and indicates that intestinal metabolism should be considered and evaluated early in drug development.

Contexte: Bien que plusieurs algorithmes pharmacogénétiques de prédiction de doses de warfarine aient été publiés, peu d’études ont comparé la validité de ces algorithmes en pratique clinique réelle. Objectif: Évaluer trois algorithmes pharmacogénomiques dans une population de patients qui initient un traitement à la warfarine et qui souffrent de fibrillation auriculaire ou de problèmes de valves cardiaques. Analyser la performance des algorithmes de Gage et al., de Michaud et al. ainsi que de l’IWPC quant à la prédiction de la dose de warfarine permettant d’atteindre l’INR thérapeutique. Méthodes: Un devis de cohorte rétrospectif fut utilisé afin d’évaluer la validité des algorithmes chez 605 patients ayant débuté une thérapie de warfarine à l’Institut de Cardiologie de Montréal. Le coefficient de corrélation de Pearson ainsi que l’erreur absolue moyenne ont été utilisés pour évaluer la précision des algorithmes. L’exactitude clinique des prédictions de doses fut évaluée en calculant le nombre de patients pour qui la dose prédite était sous-estimée, idéalement estimée ou surestimée. Enfin, la régression linéaire multiple a été utilisée pour évaluer la validité d’un modèle de prédiction de doses de warfarine obtenu en ajoutant de nouvelles covariables. Résultats : L’algorithme de Gage a obtenu la proportion de variation expliquée la plus élevée (R2 ajusté = 44 %) ainsi que la plus faible erreur absolue moyenne (MAE = 1.41 ± 0.06). De plus, la comparaison des proportions de patients ayant une dose prédite à moins de 20 % de la dose observée a confirmé que l’algorithme de Gage était également le plus performant. Conclusion : Le modèle publié par Gage en 2008 est l’algorithme pharmacogénétique le plus exact dans notre population pour prédire des doses thérapeutiques de warfarine. / Background: Although numerous genotype-based warfarin dosing algorithms have been published, there is little data comparing the predictive ability of these algorithms in real clinical practice. Objectives: Our goal was to evaluate the performance of pharmacogenetic algorithms in an unselected patient population initiating warfarin treatment for atrial fibrillation or valve disease in a real-world clinical setting. The principal objective of the analysis was to determine if Gage’s, Michaud’s, and IWPC algorithms could predict the dose achieving the therapeutic International normalized ratio (INR). Methods: Data from a retrospective cohort study of 605 patients initiating warfarin therapy at the Montreal Heart Institute was used. We compared the dose predicted by the algorithms to the dose achieving the therapeutic INR. Pearson’s correlation coefficient and mean absolute error (MAE) were used to evaluate the predictive accuracy of the algorithms. Clinical accuracy of the predictions was assessed by computing the proportion of patients in which the predicted dose was under-estimated, ideally estimated, or overestimated. Finally, we used multiple linear regression analysis to evaluate the accuracy of a predictive model obtained by adding additional covariables in predicting therapeutic warfarin doses. Results: The proportion of variation explained (adjusted R2) was the highest for Gage’s algorithm (R2 = 44 %) and the mean absolute error was the smallest for the predictions made by Gage’s algorithm (MAE = 1.41 ± 0.06). Moreover, when we compared the proportion of patients whose predicted doses are within ± 20 % of the observed stable dose, Gage’s algorithm also performed the best overall. Conclusion: The algorithm published by Gage et al. in 2008 is the most accurate pharmacogenetically based equation in predicting therapeutic warfarin dose in our study population.

No description available.

Mehrere Studien wiesen eine Beteiligung der Enzyme CYP2D6, CYP2C19 und CYP2C9 am Metabolismus von trizyklischen Antidepressiva nach. Wir untersuchten die Auswirkungen genetischer Polymorphismen dieser Enzyme auf die Pharmakokinetik von E-, Z-Doxepin und Trimipramin beim Menschen. Eine einzelne orale Dosis von jeweils 75 mg Trimipramin und Doxepin wurde 42 gesunden Probanden verabreicht, die als Schnell- (EM), Intermediär- (IM) und Langsammetabolisierer (PM) von CYP2D6- und CYP2C19-Substraten und als Langsammetabolisierer mit dem CYP2C9-Genotyp *3/*3 genotypisiert worden waren. Die Substrate sowie ihre aktiven Metaboliten wurden mittels HPLC im Plasma gemessen, Daten wurden mit nonparametrischen pharmakokinetischen Methoden analysiert und statistisch ausgewertet. Die mittlere E-Doxepin-Clearance (95%-KI) betrug 406 (390-445), 247 (241-271) and 127 (124-139) l/h bei CYP2D6-EMs, -IMs und –PMs und war auch bei Trägern des CYP2C9*3/*3-Genotyps signifikant niedriger (238 l/h). CYP2C19 beeinflusste die orale Clearance von Z-Doxepin um das 2,5-fache (73 l/h in CYP2C19-PMs verglichen mit 191 l/h bei EMs). Die AUC (0-48h) des aktiven Metaboliten Desmethyldoxepin war vom CYP2D6-Genotyp abhängig mit einem Median von 5,28, 1,35 und 1,28 nmol/l*h bei CYP2D6-PMs, -IMs und –EMs. Die mittlere orale Trimipramin-Clearance betrug 276 l/h (180-444) in der Referenzgruppe aber nur 36 l/h (24-48) bei CYP2D6-PMs. Die AUC von Desmethyltrimipramin war 40-fach höher bei CYP2D6-PMs als bei EMs (1,7 verglichen mit 0,04 mg/l*h bei EMs), aber unter der Nachweisgrenze bei den meisten Probanden mit CYP2C19- oder CYP2C9-Defizienz. Der CYP2D6-Polymorphismus wies eine starke Auswirkung auf die Pharmakokinetik von E-Doxepin und Trimipramin sowie eine ausgeprägte Stereoselektivität bei der Biotransformation von Doxepin auf. CYP2D6-PMs sind möglicherweise einem erhöhten Risiko für unerwünschte Nebenwirkungen ausgesetzt bei der Behandlung mit den EMpfohlenen Dosen dieser Antidepressiva. / Several studies have demonstrated involvement of the enzymes CYP2D6, CYP2C19 and CYP2C9 in the metabolism of tricyclic antidepressants. We studied the effects of genetic polymorphisms in these enzymes on E-,Z-doxepin and trimipramine pharmacokinetics in humans. A single orale dose of each 75 mg timipramine and doxepin was given to 42 healthy volunteers genotyped as extensive (EM), intermediate (IM) and poor (PM) metabolizers of substrates of CYP2D6 and of CYP2C19 and as slow metabolizers with the CYP2C9 genotype *3/*3. E-,Z-doxepin and -desmethyldoxepin as well as trimipramine and desmethyltrimipramine were quantified in plasma by HPLC. Data were analyzed by non-parametric pharmacokinetics and statistics. Mean E-doxepin clearance (95% confidence interval) was 406 (390-445), 247 (241-271) and 127 (124-139) l/h in EMs, IMs and PMs of CYP2D6 and was also significantly lower in carriers of CYP2C9*3/*3 (238 l/h). CYP2C19 was involved in Z-doxepin metabolism with 2.5-fold differences in oral clearances (73 l/h in CYP2C19 PMs compared with 191 l/h in EMs). The AUC (0-48 h) of the active metabolite desmethyldoxepin was dependent on CYP2D6 genotype with a median of 5.28, 1.35 and 1.28 nmol/l*h in PMs, IMs and EMs of CYP2D6. The genetically polymorphic enzymes exhibited highly stereoselective effects on doxepin biotransformation in humans. The median oral clearance of trimipramine was 276 l/h (180-444) in the reference group but only 36 l/h (24-48) in CYP2D6-PMs. The AUC of desmethyltrimipramine was 40-fold greater in CYP2D6 PMs than in the reference group (1.7 vs. 0.04 mg/l*h in EMs), but below the quantification limit in most carriers of deficiencies of CYP2C19 or CYP2C9. The CYP2D6 polymorphism had a strong impact on E-doxepin and trimipramine pharmacokinetics and CYP2D6-PMs might be at an elevated risk for adverse drug effects when treated with common recommended doses of these antidepressants.

Im Bereich der medikamentösen antidepressiven Therapie ist die Bedeutung von erblichen Polymorphismen arzneistoffmetabolisierender Enzyme bereits in vielen Studien untersucht und gezeigt worden. Die meisten Antidepressiva werden über polymorphe Cytochrom-P450-Enzyme verstoffwechselt. Diese Arbeit befasst sich mit der Fragestellung, ob die Häufigkeitsverteilung der CYP2D6-, CYP2C19- und CYP2C9-Allele in der an Depression erkrankten Studienpopulation sich von der in der Normalbevölkerung unterscheidet und ob Veränderungen in der Pharmakokinetik, wie sie durch Cytochrom-P450-Polymorphismen verursacht werden, unter normalen klinischen Bedingungen Auswirkungen auf die Wirksamkeit der antidepressiven Therapie, die Nebenwirkungsrate und den Verlauf der Erkrankung haben. Im Rahmen dieser Arbeit wurden 334 Patienten auf die häufigsten CYP2D6-Allele (*3,*4,*5,*6 und Duplikation) und CYP2C19- und CYP2C9-Allele *2 und *3 mittels Genotypisierung untersucht. Die Bestimmung der seltener auftretender CYP2D6-Allele (*8,*9,*10,*17,*2 und *41) erfolgte zusätzlich bei 200 Patienten. Die entsprechenden klinischen Fragebögen mit Angaben zur Anamnese, Schwere der Erkrankung, Therapieverlauf und Nebenwirkungsprofil wurden von 233 Patienten in Abhängigkeit des CYP2D6- und CYP2C19-Genotyps ausgewertet. Für die Beurteilung des Langzeittherapieverlaufs standen jedoch deutlich weniger Patientendaten zur Verfügung, so dass die Ergebnisse zum Teil nur für den CYPD6-Genotyp ausgewertet werden konnten. Die genetischen Analysen ergaben, dass die Häufigkeitsverteilung der CYP2D6-, CYP2C19- und CYP2C9-Polymorphismen in der untersuchten Studienpopulation keine signifikante Änderung im Vergleich zur Normalbevölkerung aufwies. Während der Einfluss der CYP2D6-Genotypen auf pharmakokinetische Parameter eindeutig nachgewiesen ist, konnten die Ergebnisse dieser Arbeit weitestgehend keinen Zusammenhang zwischen der Schwere der Depression, der Therapieresponse, der Häufigkeit und Schwere der Nebenwirkungen und dem CYP2D6- und CYP2C19-Genotyp herstellen. / The importance of genetic polymorphisms of drug metablizing enzymes have been already investigated und proved in many studies before. Most of antidepressants are metabolized by cytochrome P450 enzymes. The aim of this study was to determine if there is a difference in the distribution of CYP2D6-, CYP2C19- and CYP2C9-allels in inpatients with major depression in comparison to the healthy population and if changes in the pharmacokinatic, created by cytochrome P450 polymorphisms, can be have effects on the efficacy of antidepressant therapy, rate of intolerable side effects and development of the depression. We examined 334 patients by genotyping for the most important CYP2D6-allels (*3,*4,*6,*5 und duplication) and the CYP2C19- and CYP2C9-allels *2 and *3. Further 200 patients were tested for the more infrequent CYP2D6-allels (*8,*9,*10,*17,*2 and *41). The corresponding clinical questionnaires containing informations about the anamnesis, severity of the desease, therapeutic outcome and intolerable side effects have been evaluated of 233 patients in dependence of the CYP2D6- and CYP2C19-genotype. There were significant less clinical datas for the evaluation of long term therapy response be available, so that the results could be partially only analysed for the CYP2D6-genotype. The genetic analysis detected that the distribution of the CYP2D6-, CYP2C19- and CYP2C9-polymorphismen in the study population didn´t reached significant changes in comparison to the healthy population. While the influence of CYP2D6-genotypes on pharmacokinatic parameters is clear demonstrated, the results of this study mainly couldn´t establish a relation between the severity of depression, therapeutic response, frequency and severity of side effects and the CYP2D6 and CYP2C19-genotype.

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Made available in DSpace on 2015-07-22T20:50:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-05-26 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Introdução: Varfarina é o principal suporte no tratamento da anticoagulação oral (ACO) e na profilaxia de doenças tromboembólicas. Ela têm um índice terapêutico estreito, e é necessário regular sua monitorização para evitar efeitos adversos sérios. Existe uma ampla variabilidade interindividual na dosagem, o que torna-se imprevisível a resposta anticoagulante. Os fatores ambientais mais discutidos na literatura que afetam a resposta a anticoagulação são: a idade, o peso e altura, a dieta e interações medicamentosas. Mais recentemente, alguns polimorfismos foram estudados por contribuirem significativamente na variabilidade da dosagem de cumarina. As diferenças raciais e culturais influenciam os requisitos da dosagem, que pode ser explicado, pelo menos em parte, por fatores genéticos e alimentares. Incorporação de fatores genéticos e ambientais podem ajudar na previsão de carga mais individualizado e doses de manutenção para a terapia de anticoagulação mais segura. Materiais e método: Foram estudados 66 pacientes cardiopatas usuários de anticoagulantes orais, aplicamos um questionário induzido de frequência alimentar com 10 alimentos fonte de vit K, um recordatório de 24 hs / habitual, orientamos o paciente para uma ingestão de vit K regular ou até 500 μg/dia e um registro Alimentar de 7 dias. Observamos a dose diária do ACO; acompanhamos 10 valores de INR antes e após a orientação nutricional; análise da Vitamina K sérica e polimorfismo do CYP2C9. Resultados: O consumo habitual de vitamina K1 antes da orientação nutricional foi em média de 80,95 ± 82,37 μg/dia e após a orientação nutricional o resultado foi de 64,03 ± 39,77 μg/dia. Analisando o QFA do nosso estudo, o consumo da vitamina K1 estava abaixo do recomendado. Na avaliação sobre o tipo de óleo, o consumo do óleo de soja foi maior. Os valores achados de vitamina K1 plasmática na nossa população foram em média de 0,55 ± 0,52 ng/mL. No nosso estudo, não foi observada uma correlação entre o aumento ou diminuição da ingestão da vitamina K1 e o INR que sustentasse essa relação. Na análise da genotipagem para o polimorfismo no CYP2C9, foi observado 46 (69%) pacientes com o tipo selvagem *1/*1, com dose média de 3,16 ± 1,69 mg/dia; 13 (20%) dos pacientes com genótipo *1/*2, dose média de 3,28 ± 2,23 mg/dia; 5 (7%) dos pacientes com genótipo *1/*3, com dose média de 2,24 ± 0,65 mg/dia e 2 (3%) dos pacientes com genótipo *2/*2, com dose média de 3,03 ± 1,26 mg/dia. Conclusão: A variabilidade das necessidades da dose de warfarina é multifatorial. A abordagem dietoterápica para pacientes em uso de anticoagulante oral deve ser individualizada, o papel da equipe multidisciplinar poderá interferir positivamente no controle da atividade anticoagulante para um tratamento mais seguro, assim como melhores condições de alimentação e nutrição. A incorporação de fatores genéticos e ambientais pode ajudar na previsão e manutenção da dose individualizada. / Introduction: Warfarin is a mainstay in the treatment of oral anticoagulation and prophylaxis of thromboembolic illness. It has a narrow therapeutic index, and it’s important to regulate it’s monitoring to avoid serious adverse effects. There is a wide variety of dose applications, which makes the anticoagulant responses unpredictable. The environmental factors discussed in the literature that most affect the response to anticoagulation are: age, height and weight, diet and drug interactions. Recently, several polymorphisms were studied for contributing significantly in the dosage variability of coumarin. The racial and cultural differences have influence in the dosage requirements, which can be explained, at least in part, by genetic factors and eating habits. The study of genetic and environmental factors may help in predicting a more personal applying and maintenance of the doses for a safer anticoagulation therapy. Methods and Materials: We studied 66 heart patients users of oral anticoagulants, and applied a food frequency questionnaire with 10 food sources of vitamin K, a period of 24 hours / usual, we guide the patient to a regular intake of vitamin K or even 500 μg / day and a seven day food record. We observed the daily dose of OAC; followed 10 RNI values before and after nutritional counseling, analysis of serum vitamin K and polymorphism of CYP2C9. Results: The regular consume of vitamin K1 prior to nutritional counseling averaged 80.95 ± 82.37 μg / day and after nutritional counseling, the result was 64.03 ± 39.77 μg / day. Analyzing the FFQ (food frequency questionnaire) in our study, consumption of vitamin K1 was lower than recommended. In evaluating the type of oil, the consumption of soybean oil was higher. The values of vitamin K1 plasmatic found in our population averaged 0.55 ± 0.52 ng/mL. In our study, there was no correlation between increased or decreased consume of vitamin K1 and the RNI in support of this relationship. In the analysis of genotyping for polymorphism in CYP2C9 was observed 46 (69%) patients with wild type * 1 / * 1, with an average dose of 3.16 ± 1.69 mg / day; 13 (20%) patients with genotype * 1 / * 2, with an average dose of 3.28 ± 2.23 mg / day, 5 (7%) patients with genotype * 1 / * 3, with an average dose of 2.24 ± 0.65 mg / and day 2 (3%) patients with genotype * 2 / * 2, with an average dose of 3.03 ± 1.26 mg / day. Conclusion: The variability in dose requirements of warfarin is multifactorial. The dietary approach to patients using oral anticoagulants should be individualized, the role of the multidisciplinary team can positively affect the control of anticoagulant activity for a safer treatment, as well as improving eating habits and nutrition. The incorporation of genetic factors can help to predict and maintain the individualized dose. / TEDE / BV UNIFESP: Teses e dissertações