Uticaj genske varijabilnosti adrenergičkih receptora i citohroma P450 oksidaze na farmakokinetiku i terapijsku efikasnost beta blokatora kod pacijenata sa srčanom insuficijencijom

Abstract

The beta-adrenergic receptor (β-AR) pathway is altered in heart failure. Recent studies have discovered functionally relevant and common polymorphisms in both β1-AR and β2-AR. These polymorphisms have been implicated with inconsistent results in the pathogenesis, clinical presentation, and prognosis of patients with heart failure (HF). In patients with HF, β-blockers reduce mortality. It’s not known whether the the response to β blockers in patients with HF could be associated with the genotype of drug-metabolizing enzymes and/or drug targets. We investigated the correlation of adrenergic receptor polymorphisms β1Ser49Gly, β1Arg389Gly and β2Arg16Gly with the risk of HF in Serbian population using a casecontrol study design. The genotype frequencies were in Hardy-Weinberg equilibrium. These polymorphisms were analysed by polymerase chain reaction-restriction fragment length polymorphism in patients with HF and compared with the control group. We also investigated the impact of 3 functional polymorphisms on survival, hospitalization and emergency department (ED) visits due to HF in carvedilol- and bisoprolol-treated HF patients. For these propose, 70 patients were enrolled and followed up at the HF clinic, and vital status was evaluated using electronic hospital and emergency department records and a local death certificate database. The aim of this study was to derive population pharmacokinetic (PK) model for clearance (CL) of carvedilol and bisoprolol, respectively in adult patients with HF using non-linear mixedeffect modeling (NONMEM). Finally, purpose of this study was to determine whether genetic polymorphisms in CYP2D6 correlated with dose of, or response to, bisoprolol or carvedilol treatment in patients with HF. Carvedilol and bisoprolol concentrations were quantified and effects on resting heart rate and blood pressure were analyzed using a multivariable clinical-genetic analysis. There were no differences or any trends in the allele and genotype frequencies of the β1Ser49Gly, β1Arg389Gly and β2Arg16Gly polymorphisms. None of these polymorphisms were associated with adverse outcomes (hospitalization, ED visits or mortality). There were significant CYP2D6 allele-specific differences in carvedilol pharmacokinetics, but the CYP2D6 genotype had no effect on heart rate and blood pressure. Our population pharmacokinetic (PPK) model for the clearance of carvedilol in routinely treated adult patients with CHF showed that the total body weight, concomitant therapy with digoxin and smoking tobacco were the main subjects of carvedilol pharmacokinetic variability. Finally, PPK model for the clearance of bisoprolol showed that the total daily dose of bisoprolol was the only important covariate. In conclution, β-blockers are the drugs where CYP2D6-related pharmacokinetic variation is apparently not carried forward into pharmacodynamic variation. Although current knowledge does not allow utilizing β1-AR and β2-AR genotypes for clinical treatment decisions, our data should stimulate further research on the impact of these genotypes in health and disease.