Circulating miR-320a-3p and miR-483-5p level associated with pharmacokinetic–pharmacodynamic profiles of rivaroxaban

Abstract

Background Novel biomarkers for personalizing anticoagulation remain undetermined. We aimed to investigate the association of plasma miRNAs with pharmacokinetic–pharmacodynamic (PK-PD) profiles of rivaroxaban. Methods This is a multicenter, exploratory study of miRNAs in a Chinese population. Healthy volunteers and patients receiving rivaroxaban were enrolled in the study. The area under the plasma concentration–time curve from time 0-t h (AUC0-t) and anti-Xa activity at 3 h (AXA3h) were measured in healthy volunteers, and AXA3h was measured in patients. MiRNAs were detected by miRNA microarray in 26 healthy volunteers with 20 mg rivaroxaban, and quantitative reverse transcription polymerase chain reaction was used to exclude undetectable ones. MiR-320a-3p and miR-483-5p were then quantified in 65 healthy volunteers and 71 patients. MiRNA levels at 3 h were compared between high and low AXA3h or AUC0-t subjects and in matched patients with or without bleeding during follow-up. The miRNA targets were predicted by TargetScan, miRTarBase, and miRDB. Validated genes were included in GO enrichment and KEGG analyses. The protein–protein interaction network was established by STRING and visualized by Cytoscape. Results A total of 136 Chinese subjects completed the study. In healthy volunteers taking 15 mg rivaroxaban, the miR-320a level at 3 h was significantly positively correlated with AXA3h and AUC0-t (r = 0.359, p = 0.025; r = 0.370, p = 0.02, respectively). A positive correlation was also observed between miR-483 and AXA3h or AUC0-t (r = 0.372, p = 0.02; r = 0.523, p = 0.001, respectively). MiR-320a and miR-483 levels at 3 h in the higher AUC0-t group were significantly higher than those at 0 h. MiR-483 levels at 3 h may distinguish healthy volunteers with high or low AXA3h or AUC0-t. In the 10 mg fed subgroup, higher 3 h mir-483 levels were also observed compared with the control group. No significant differences were found in the comparisons among patients. Bioinformatic analysis showed that these miRNAs may play a regulatory role by targeting ABCG2, ITGB3, PTEN, MAPK1/3, etc. Conclusions MiR-320a and miR-483 levels were found to be associated with PK and PD profiles of rivaroxaban in healthy Chinese subjects. Further studies are required to verify these findings and explore the mechanisms.

DNA and RNA Molecules as a Foundation of Therapy Strategies for Treatment of Cardiovascular Diseases

“…MiRNAs in circulation have been shown to indicate the status of thrombocytes in real time and that they can be used as biomarkers for the prediction of various aspects of their function, i.e., they can be used for monitoring and adjusting anti-aggregation therapy [ 46 , 47 ]. Additionally, it has been confirmed that miRNAs affect anticoagulation therapy with coumarin derivatives [ 48 ], therapy with direct anticoagulation drugs [ 49 ], and that they also affect therapy with statins, i.e., statin intolerance [ 50 ]. The predictive potential of long non-coding RNAs has also been recognised for the effects of anti-aggregation therapy [ 51 ].…”

Integrative bioinformatics and validation studies reveal KDM6B and its associated molecules as crucial modulators in Idiopathic Pulmonary Fibrosis

“…The ceRNA network analysis was conducted for assessing the miRNA-mRNA interactions. The TargetScan (25), miRNet (26), and miRWalk (27) databases were used to identify probable miRNAs that target hub genes. If the same data was retrieved from every database simultaneously, accurate results were produced.…”

Circulating microRNAs and DNA Methylation as Regulators of Direct Oral Anticoagulant Response in Atrial Fibrillation and Key Elements for the Identification of the Mechanism of Action (miR-CRAFT): Study Design and Patient Enrolment

“…The expression profile of miRs and DNA methylation in AF patients treated with DOACs has been scarcely studied. It was just recently found that miR-320a and miR-483 levels are associated with the pharmacokinetic and pharmacodynamic profiles of rivaroxaban [ 25 ], whereas no studies are currently available on the potential association between DOAC therapy and alterations in DNA methylation levels. It appears, thus, that DOAC epigenomics is a naïve, albeit crucial in mechanism identification, field of research.…”