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Background and Objective: There is an unmet need for a safer anticoagulant since bleeding remains a concern with currently approved anticoagulants. Coagulation factor XI (FXI) is an attractive anticoagulant drug target with limited a role in physiological hemostasis. The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of SHR2285, a novel small molecule FXIa inhibitor, in healthy Chinese volunteers. Methods: The study consisted of single ascending doses part (part 1: 25–600 mg) and multiple ascending doses part (part 2: 100, 200, 300, and 400 mg). In both parts, subjects were randomized in a 3:1 ratio to receive SHR2285 or placebo orally. Blood, urine and feces samples were collected to describe its pharmacokinetic and pharmacodynamic profile. Results: In total, 103 healthy volunteers completed the study. SHR2285 was well tolerated. SHR2285 was absorbed rapidly with median time to maximum plasma concentration (Tmax) of 1.50 to 3.00 h. The geometric median half-life (t1/2) of SHR2285 varied from 8.74 to 12.1 h across 25–600 mg single dose. Total systemic exposure of metabolite SHR164471 was approximately 1.77- to 3.61-fold that of the parent drug. The plasma concentration of SHR2285 and SHR164471 reached steady state by the morning of Day 7, with low accumulation ratio (0.956–1.20 and 1.18–1.56, respectively). The increase in pharmacokinetic exposure of SHR2285 and SHR164471 was less than dose proportional. Food has minimal effect on the pharmacokinetics of SHR2285 and SHR164471. SHR2285 produced an exposure-dependent prolongation of activated partial thromboplastin time (APTT) and a decrease in FXI activity. The maximum FXI activity inhibition rate (geometric mean) at steady state was 73.27%, 85.58%, 87.77% and 86.27% for 100–400 mg, respectively. Conclusions: SHR2285 was generally safe and well tolerated in healthy subjects across a wide range of doses. SHR2285 exhibited a predictable pharmacokinetic profile and an exposure-related pharmacodynamic profile. ClinicalTrials.gov Identifier NCT04472819; registered on July 15, 2020. [ABSTRACT FROM AUTHOR]

Introduction: To identify the potential factors responsible for the individual variability of dabigatran, we investigated the genetic variations associated with clinical outcomes and pharmacodynamics (PD) in Chinese patients with nonvalvular atrial fibrillation (NVAF). Materials and methods: Chinese patients with NVAF taking dabigatran etexilate with therapeutic doses were enrolled. The primary (bleeding events) and secondary (thromboembolic and major adverse cardiac events) outcomes for a 2‐year follow‐up were evaluated. Peak and trough PD parameters (anti‐FIIa activity, activated partial thromboplastin time and prothrombin time) were detected. Whole‐exome sequencing, genome‐wide sequencing and candidate gene association analyses were performed. Results: There were 170 patients with NVAF treated with dabigatran (110 mg twice daily) who were finally included. Two single‐nucleotide polymorphisms (SNPs) were significantly related with bleeding, which include UBASH3B rs2276408 (odds ratio [OR] = 8.79, 95% confidence interval [CI]: 2.99–25.83, p = 7.77 × 10−5 at sixth month visit) and FBN2 rs3805625 (OR = 8.29, 95% CI: 2.87–23.89, p = 9.08 × 10−5 at 12th month visit), as well as with increased trends at other visits (p <.05). Furthermore, minor allele carriers of 16 new SNPs increased PD levels, and those of one new SNP decreased PD values (p < 1.0 × 10−5). Lastly, 33 new SNPs were found to be associated with bleeding and PD among 14 candidate genes. Unfortunately, the low number of secondary outcomes precluded further association analyses. Conclusions: Genetic variations indeed affected bleeding and PD in Chinese patients with NVAF treated with dabigatran. The functions of these suggestive genes and SNPs might further be explored and verified in more in vivo and in vitro investigations. [ABSTRACT FROM AUTHOR]

(1) Background: The purpose of this study was to evaluate the effect of gene polymorphisms on prothrombin time (PT) and activated partial thromboplastin time (APTT) in a healthy Chinese population. (2) Methods: A total of 403 healthy volunteers from a series of novel oral anticoagulants (NOACs) bioequivalence trials in China were included. Coagulation tests for PT and APTT were performed in the central lab at Peking University First Hospital. Whole-exome sequencing (WES) and genome-wide association analysis were performed. (3) Results: In the correlation analysis of PT, 105 SNPs from 84 genes reached the genome-wide significance threshold (p < 1 × 10−5). Zinc Finger Protein 594 (ZNF594) rs184838268 (p = 4.50 × 10−19) was most significantly related to PT, and Actinin Alpha 1 (ACTN1) was found to interact most with other candidate genes. Significant associations with previously reported candidate genes Aurora Kinase B (AURKB), Complement C5(C5), Clock Circadian Regulator (CLOCK), and Histone Deacetylase 9(HDAC9) were detected in our dataset (p < 1 × 10−5). PiggyBac Transposable Element Derived 2(PGBD2) rs75935520 (p = 4.49 × 10−6), Bromodomain Adjacent To Zinc Finger Domain 2A(BAZ2A) rs199970765 (p = 5.69 × 10−6) and Protogenin (PRTG) rs80064850 (p = 8.69 × 10−6) were significantly correlated with APTT (p < 1 × 10−5). The heritability values of PT and APTT were 0.83 and 0.64, respectively; (4) Conclusion: The PT and APTT of healthy populations are affected by genetic polymorphisms. ZNF594 and ACTN1 variants could be novel genetic markers of PT, while PRTG polymorphisms might be associated with APTT levels. The findings could be attributed to ethnic differences, and need further investigation. [ABSTRACT FROM AUTHOR]

Background: For patients taking factor Xa (FXa) inhibitors who have life-threatening bleeding, emergency surgery, drug interactions, etc., a rapid and precise assay is needed to monitor for potential medication failure, to assess safety during periprocedural anticoagulation management, and to manage the care of chronically anticoagulated patients. Anti-factor Xa (anti-Xa) activity assays have been recommended in guidelines, but the evaluation of different calibrations of anti-Xa activity assays and the data on the recommended range are still limited, especially in the Asian population. Methods: This is a nationwide multicenter methodology exploratory study in an Asian population, including nine hospitals from Beijing, Shanghai, Liaoning, Shandong, Jiangsu, Anhui, Henan, Chongqing, and Fujian. A total of 485 healthy volunteers and 219 patients taking rivaroxaban or apixaban (single dose) were enrolled in the study. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) was employed to detect plasma rivaroxaban and apixaban. The prothrombin time (PT), activated partial thromboplastin time (APTT), and levels of anti-Xa activity were tested as pharmacodynamic parameters in plasma samples. We evaluated the correlation of anti-Xa activity and blood concentration via HPLC-MS, and then compared the two methods of target drug-calibrated and low-molecular-weight heparin (LMWH)-antithrombin–calibrated anti-Xa activity. Correlations between variables were examined using Pearson's correlation analysis. Logistic regression was applied to evaluate significant differences in anti-Xa activity and blood concentration, using models adjusted by baseline characteristics. Results: The results suggested anti-Xa activity had better correlation with blood concentrations of apixaban and rivaroxaban than APTT and PT (p < 0.001). Target drug-calibrated anti-Xa activity had better correlation with HPLC-MS results at every dose level and blood collection time (p < 0.001). The expected concentrations (ng/mL) derived from rivaroxaban-calibrated assays of rivaroxaban 10 mg, 15 mg, and 20 mg were about 210, 330, and 270 at peak concentrations, and 28, 44, and 58, respectively, at the trough concentrations. Conclusions: In this study, we confirm that target drug calibration of anti-Xa activity is a better quantitative detection method for oral direct FXa inhibitors than LMWH-calibrated anti-Xa activity in clinical practice, and expected peak–trough levels are recommended for the Asian population. [ABSTRACT FROM AUTHOR]