Towards optimal dosing of coumarin derivatives: the role of pharmacogenetics

摘要: Coumarin derivatives are effective in the prevention and treatment of thromboembolic diseases. Examples indications atrial fibrillation venous thromboembolism. Although coumarins on market for decades, it is still challenging to find optimal dosage each patient since have a small therapeutic index. In trying achieve anticoagulant effect, constantly balances between too low effect -which increases risk events- high hemorrhages. addition, there wide inter- intra-patient variability coumarin dose requirements. A that provides anticoagulation status first might cause hemorrhages second events third. this thesis, we describe studies aimed develop pretreatment personalized dosing strategies coumarins. general introduction history pharmacogenetics oral therapy with provided Chapter 1 Part I, 2. II, discuss development usage nongenotype- genotype-guided algorithms phenprocoumon acenocoumarol. The validation acenocoumarol described 3. We include information age, height, weight, sex, amiodarone use nongenotype-guided algorithm. algorithm includes next these VKORC1 genotype CYP2C9 genotype. explains 55.9% 52.6% variance maintenance acenocoumarol, respectively while percentages were 17.3% 23.7%, respectively. Validation Rotterdam study cohort, has showed equal performance (Chapter 4). Subsequently, tested randomized controlled trial: European Pharmacogenetics Anticoagulant Therapy (EU-PACT) trial, which design presented 5. Effects genetic comedication III, chapter 6-9. evaluate possible gene-gene interaction variations GATA-4 (the gene encoding transcription factor), CYP3A4*1B, CYP3A4*22, CYP4F2 V433M statin dose. most promising findings decreased but not phenprocoumon, requirements patients who concurrently atorvastatin, simvastatin, pravastatin or rosuvastatin. 10 elaborate thesis. main discussed placed broader perspective. It argued how implement clinical setting parties involved. facilities required implementation considered cost-effectiveness technical developments discussed. Finally, recent regarding new anticoagulants (NOACs) suggestions future research