Background: Non-vitamin K oral anticoagulants (NOACs) are commonly used for prophylaxis of venous thromboembolism (VTE) in orthopedic patients. Despite known safety and high potency of NOACs, potential interactions of NOACs with genetic polymorphisms are poorly understood. Dabigatran etexilate is one of the most commonly prescribed direct thrombin inhibitors for the prevention of VTE. The objectives of this study were to assess the effect of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) polymorphisms on dabigatran pharmacokinetics in patients after total knee arthroplasty. Patients and methods: A total of 60 patients, aged 37–81 years, who underwent surgery for knee replacement have been included in the study. VTE prophylaxis was conducted via administration of dabigatran etexilate 220 mg once daily. Genotyping for carrier state of polymorphic variants such as rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene was carried out using real-time polymerase chain reaction (PCR). We also measured the peak and trough concentrations of plasma dabigatran by using high-performance liquid chromatography (HPLC). Results: Our study revealed that TT genotype of rs1045642 polymorphism of the ABCB1 gene was associated with higher dabigatran equilibrium peak concentrations and the higher risk of bleeding than the presence of CC genotype (p<0.008). There was no statistically significant genotype-dependent difference in the trough concentrations between rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene. Conclusion: Our findings indicate that the polymorphisms of ABCB1 rs1045642 may have a prominent contribution to the safety of dabigatran in patients after knee surgery. Moreover, TT genotype may be associated with the higher risk of hemorrhagic complications in this population. There were no influence of polymorphism of ABCB1 rs4148738 and CES1 rs2244613 on dabigatran peak and through concentrations. Larger studies are needed to confirm our observations.

To describe polymyxin B pharmacokinetics in patients receiving veno-venous extracorporeal membrane oxygenation (ECMO) in comparison with critically ill patients without ECMO support and to explore potential covariates that could affect the pharmacokinetics in this group of patients. In 13 critically ill patients on ECMO and in 21 critically ill patients without ECMO support, 6–8 blood samples were collected during 12 h intervals after reaching steady state. Polymyxin B concentration in serum was determined using a previously developed ELISA. Protein binding was assessed by rapid equilibrium dialysis. In 13 critically ill patients on ECMO who received polymyxin B, the median area under the concentration–time curve over 12 h (AUC_0–12h) was 48.38 mg/h/L for the total drug and 14.08 mg/h/L for the free drug. The unbound fraction was 0.35. Total body clearance was 1.16 L/h. In non-ECMO patients, the median AUC_0–12h was 34.7 mg/h/L and the median CL was 1.76 L/h. The volume of distribution was significantly lower in ECMO patients (19.7 versus 30.4 L, respectively). We found a moderate negative correlation between the ECMO blood flow rate and AUC_0–12h, a strong negative correlation between SOFA score and polymyxin B clearance and a moderate correlation between polymyxin B clearance and renal function in ECMO patients. Currently recommended polymyxin B dosage regimens are sufficient for patients receiving ECMO and no dosage increase is required. In our study, polymyxin B exposure was higher in ECMO patients compared with the control group.

Introduction: The aim of this study is to assess the influence of gene CYP2C19, CYP3A4, CYP3A5 and ABCB1 polymorphisms on clopidogrel antiplatelet activity, rivaroxaban concentration equilibrium, and clinical outcomes among patients with acute coronary syndrome and non-valvular atrial fibrillation. Methods: In the multicenter prospective registry study of the efficacy and safety of a combined antithrombotic therapy 103 patients with non-valvular atrial fibrillation both undergoing or not a percutaneous coronary intervention were enrolled. The trial assessed the primary outcomes (major bleeding, in-hospital death, cardiovascular death, stroke ransient ischaemic attack, death/renal insufficiency) and secondary outcomes (platelet reactivity units (PRU), rivaroxaban concentration). Results: For none of the clinical outcomes when combined with other covariates, the carriership of polymorphisms CYP3A5*3 rs776746, CYP2C19*2 rs4244285;*17 rs12248560, ABCB1 3435 C>T, ABCB1 rs4148738 was significant. None of the markers under study (CYP3A5*3 rs776746, CYP2C19*2 rs4244285, *17 rs12248560, ABCB1 3435 C>T, ABCB1 rs4148738) has proven to affect rivaroxaban equilibrium concentration in blood plasma among patients with atrial fibrillation and acute coronary syndrome. Conclusion: In situations of double or triple antithrombotic rivaroxaban and clopidogrel therapy among patients with atrial fibrillation and acute coronary syndrome, the genetic factors associated with bleeding complications risk (CYP2C19*17) may prove to be clinically relevant.

Objectives: For revealing the peculiarities of the drug–drug interaction of rivaroxaban (substrate CYP3A4 and P-gp) and calcium channel blockers (CCBs) (verapamil – inhibitor CYP3A4 and P-gp and amlodipine – substrate CYP3A4) in patients 80 years and older with nonvalvular atrial fibrillation (NAF) we studied 128 patients. Methods: All patients were divided into groups depending on the therapy taken: the 1st – rivaroxaban + amlodipine (n=51), the 2nd – rivaroxaban + verapamil (n=30), the control group – rivaroxaban without CCBs (n=47). A trough steady-state plasma concentration (C _min,ss) of rivaroxaban, prothrombin time (PT) in the blood plasma and the event of clinically relevant non-major (CRNM) bleeding were assessed for each patient. Results: Patient in group 2 had higher C _min,ss of rivaroxaban, PT and CRNM than subjects in the control group (Me 73.8 [50.6–108.8] ng/mL vs. 40.5 [25.6–74.3] ng/mL; Me 14.8 [13.4–17.3] s vs. 13.8 [12.6–14.4] s; 34% vs. 13%, respectively, p0.05 for all). Conclusions: In patients ≥80 years with NAF, the use of rivaroxaban in combination with verapamil may not be safe and can lead to CRNM bleeding.

Aim. To study the possible relationship between polymorphic variants of ABCB1 (rs2032582, rs1045642, rs1128503), CYP3A5 (rs776746), CYP3A4 (rs35599367) and CYP2J2 (rs890293) genes with residual equilibrium concentrations (Cmin,ss) of rivaroxaban in patients with non-valvular atrial fibrillation (AF) and stage 3 and 4 chronic kidney disease (CKD).Material and methods. A total of 123 patients 52 to 97 years old (median age, 82 years) with AF in combination with stage 3 and 4 CKD were included in the study. Each patient underwent a pharmacogenetic and pharmacokinetic study.Results. Cmin,ss and dose-adjusted concentration (Cmin,ss/D) of rivaroxaban were significantly higher in patients with the TT genotype than with the CT genotype of the polymorphic variant rs1045642 of the ABCB1 gene (Сmin,ss 60,5 [36,7;173] ng/ml and 54,8 [23,1;97,3] ng/ml, respectively, р=0,016; Сmin,ss/D 4,06[2,3;8,1] ng/ml/mg and 2,2 [1,1;4,9] ng/ml/mg, р=0,006). In patients with the T allele (CT and TT genotypes), compared with CC genotype carriers, Cmin,ss and Cmin,ss/D were significantly higher (Cmin,ss 60,5 [36,7;173] ng/ml and 45,8 [20,9;82,3] ng/ml, respectively, p=0,029; Cmin,ss/D 4,06 [2,3;8,1] ng/ml/ mg and 2,6 [1,2;4,8] ng/ml/mg, respectively, p=0,014). Also, Cmin,ss and Cmin,ss/D was significantly higher in patients with the TT genotype according to the polymorphic variant rs2032582 of the ABCB1 gene than in patients with the GG genotype (p=0,02 and р=0,016 respectively). Cmin,ss and Cmin,ss/D in T allele (GT and TT genotypes) carriers were significantly higher than in T allele homozygotes (Cmin,ss 57,1 [27,7;106,0] ng/ml versus 37,6 [18,6;61,7] ng/ml respectively, p=0,024; Cmin,ss/D 3,6 [1,7;7,4] ng/ml/mg versus 2,3 [1,1;4,09] ng/ml/mg respectively, p=0,032). Differences in Сmin,ss and Сmin,ss/D of rivaroxaban were detected when comparing TC, CC and TT genotypes of polymorphism rs1128503 of the ABCB1 gene. When comparing Сmin,ss and Сmin,ss/D of rivaroxaban among carriers of AG and GG genotypes of the rs776746 polymorphism of the CYP3A56986A>G gene, no significance was detected (p>0,05). Also, no difference in Cmin,ss and Cmin,ss/D was found when comparing carriers of the CC and CT genotypes of the rs35599367 polymorphism of the CYP3A4 gene, and carriers of the CC and AC genotypes of the rs890293 polymorphism of the CYP2J2 gene (p>0,05).Conclusion. The carriage of T allele by polymorphic variants rs1045642 and rs2032582 of the ABCB1 gene affects Cmin,ss and Cmin,ss/D of rivaroxaban.

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with a fivefold increase in stroke risk. Direct oral anticoagulants (DOACs), including apixaban, are now the preferred therapy for stroke prevention in patients with non-valvular AF (NVAF). However, interindividual variability in drug response and safety remains a major challenge, particularly in elderly patients with comorbidities and polypharmacy. Genetic polymorphisms in drug-metabolizing enzymes and transporters may contribute to variability in apixaban exposure and bleeding risk. This study aimed to evaluate the association of polymorphisms in ABCB1, CYP3A4, and CYP3A5 with steady-state plasma concentrations of apixaban (Cssmin) and hemorrhagic complications in elderly patients with NVAF. Methods: This cross-sectional study included 197 patients (mean age 83 ± 8 years; 67% women) with NVAF treated with apixaban (5 mg twice daily). Genotyping of ABCB1 (rs1045642, rs2032582, rs1128503), CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746) was performed using allele-specific real-time PCR. Cssmin of apixaban was determined by high-performance liquid chromatography coupled with tandem mass spectrometry. Associations with bleeding events were evaluated. Results: Bleeding events were recorded in 40 patients (20.3%). An association signal was observed for ABCB1 rs1045642, where carriers of the CC genotype had a higher risk of bleeding compared with alternative alleles (OR = 2.805; 95% CI: 1.326–5.935; p = 0.006). After correction for multiple testing, the association remained significant only under the log-additive model (OR = 1.93 per C allele; 95% CI: 1.17–3.20; q = 0.0275; p_adj = 0.044), while recessive and codominant effects did not withstand Bonferroni adjustment. No significant associations were observed for rs2032582, rs1128503, CYP3A4*22, or CYP3A5*3. None of the studied polymorphisms, including rs1045642, significantly affected Cssmin. Concomitant therapy, particularly with antiarrhythmic drugs and statins (rosuvastatin), also increased bleeding risk. Conclusions: The findings highlight the potential contribution of ABCB1 rs1045642 and specific drug–drug interactions to the risk of hemorrhagic complications in elderly NVAF patients receiving apixaban.