Utjecaj kombinacije polimorfizma gena CYP2C9, VKORC1 i MDR1 na individualizaciju terapije varfarinom [Influence of combination of CYP2C9, VKORC1 and MDR1 gene polymorphisms on individualization of warfarine therapy]

Makar-Aušperger, Ksenija (2015) Utjecaj kombinacije polimorfizma gena CYP2C9, VKORC1 i MDR1 na individualizaciju terapije varfarinom [Influence of combination of CYP2C9, VKORC1 and MDR1 gene polymorphisms on individualization of warfarine therapy]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Despite that warfarine has been used as an anticoagulant for many years it's dosing presents a challenging task owing to its narrow therapeutic range and large variability in dose-response relationship. Warfarine therapy usually started after assessment of clinical characteristics (age, body size, race), vitamin K intake and use of concomitant medications. Inappropriate dosing continues to contribute to significant morbidity and mortality due to thrombotic disease and bleeding complications. Genetic variations in the cytochrome P450 polypeptide 9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) have been identified as the most important enzymes in the warfarin pharmacological pathway. Observational studies have indicated CYP2C9, VKORC1 and MDR1 potential effect but randomized clinical trials resulted in contradictory findings. The aim of this study is to evaluate the influence of combination of CYP2C9, VKORC1 and MDR1 gene polymorphisms on individualization of warfarine therapy. We have not found statistically significant benefits from genotype guided dosing in deep-vein thrombosis and pulmonary embolism, but in atrial fibrillation percentage of time with INR therapeutic range was statistically significantly longer in this, than in clinically guided dosing group. Stable dose was achieved by statistically significantly larger number of patients whose dose had been determined by genotype and clinical characteristics than in clinically-only-guided dosing group.

Abstract in Croatian

Varfarin, iako lijek koji se jako dobro poznaje još uvijek zahtijeva vrlo pažljivu primjenu zbog svojih posebnosti - uskog terapijskog indeksa i velike varijabilnosti odnosa doze i učinka. Uvođenje varfarina do sada se temeljilo uglavnom na kliničkim parametrima svakog bolesnika: dobi, spolu, popratnim bolestima, tjelesnoj težini, a doza i učinak značajno ovise i o istodobnoj primjeni lijekova. Ipak u velikog dijela bolesnika stabilizacija parametara koagulacije i stabilizacija doze se ne postiže brzo. Opasnost od krvarenja kao i opasnost od ponovne tromboze je i dalje velika. Polimorfizam gena uključenih u farmakodinamiku (VKORC1) i farmakokinetiku (CYP2C9) varfarina mogu velikim dijelom objasniti individualne zahtjeve za dozom. Novija istraživanja ukazuju da bi i polimorfizam MDR1 gena mogao utjecati na indvidualizaciju doze jer P-glikoprotein kao transportni protein moguće ima važnu ulogu u raspoloživosti varfarina. Cilj ovog istraživanja bio je procijeniti učinak kombinacije polimorfizama sva tri gena na dozu primijenjenog varfarina. Nije utvrđena statistička značajnost genotipiziranog vođenja doziranja u bolesnika s dubinskovenskom trombozom i plućnom embolijom no ona je potvrđena u bolesnika s atrijskom fibrilacijom. Stabilna doza postignuta je u velikog broja bolesnika s genotipizacijom u odnosu na one s kliničkim vođenjem terapije.

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