Impact of Biomarkers on Pharmacokinetics and Pharmacodynamics of Direct Oral Anticoagulants

It is general that there are many factors for individual differences of drugs in clinical application, of which genetic factors accounted for more than 20%. Novel oral anticoagulants-NOACs (include rivaroxaban, apixaban, dabigatran and so on) have advantages of convenient use and no need of monitoring, compared with the traditional vitamin K antagonist. With lack of predicted biomarkers, especially the research data of Chinese, it has the important significance in studying individual differences of NOACs in the anticoagulant efficacy and safety, through the pharmacogenomics research.

The aim of this study is to determine the polymorphism of drug metabolizing enzymes, drug transporters and drug target genes in Chinese population. By detecting the gene polymorphism, we intend to study the pharmacokinetic/ pharmacodynamics/ pharmacogenomics (PK-PD-PG) correlation of NOACs and provide scientific basis for accurate medication guide for people to use NOACs.

Study Overview

• Status: Unknown
• Conditions: Pharmacokinetics; Pharmacodynamics; Apixaban; Pharmacogenomics; Accurate Medication; Rivaroxaban; Novel Oral Anticoagulants; NOACs; Dabigatran
• Intervention / Treatment: Genetic: detection of genotype

• Study Type: Observational
• Enrollment (Anticipated): 1200

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China, 230001
      • Recruiting
      • Anhui Provincial Hospital（The First Affiliated Hospital Of USTC）
  • Beijing
    • Beijing, Beijing, China, 100034
      • Recruiting
      • Peking University First Hospital
    • Beijing, Beijing, China, 100730
      • Recruiting
      • Beijing Hospital
      • Contact: Yatong Zhang, MS; Phone Number: +86-010-85133637; Email: zyt2002888@qq.com
    • Beijing, Beijing, China
      • Active, not recruiting
      • Beijing HuiLongGuan Hospital
  • Chongqing
    • Chongqing, Chongqing, China, 400010
      • Recruiting
      • The Second Affiliated Hospital of Chongqing Medical University
  • Fujian
    • Fuzhou, Fujian, China, 350000
      • Active, not recruiting
      • Fujian Medical University Union Hospital
    • Fuzhou, Fujian, China
      • Recruiting
      • 900 Hospital of the Joint Logistics Team (Original name: Fuzhou General Hospital of Nanjing Militray Command)
  • Henan
    • Zhengzhou, Henan, China
      • Recruiting
      • The 7th People's Hospital of Zhengzhou
      • Contact: Dongdong Yuan, MS; Phone Number: 0371-89905878; Email: 44676878@qq.com
  • Hunan
    • Changsha, Hunan, China
      • Active, not recruiting
      • The Third Hospital of Changsha
  • Jiangsu
    • Wuxi, Jiangsu, China, 214023
      • Withdrawn
      • Wuxi People's Hospital
    • Wuxi, Jiangsu, China
      • Active, not recruiting
      • The Affiliated Hospital of Jiangnan University, or called Original Wuxi Third Hospital
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • Active, not recruiting
      • The First Affiliated Hospital of Nanchang University
  • Liaoning
    • Shenyang, Liaoning, China, 110032
      • Active, not recruiting
      • The First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine
  • Neimenggu
    • Hohhot, Neimenggu, China
      • Recruiting
      • The Affiliated Hospital of Inner Mongolia Medical University
      • Contact: Jianjun Sun, PhD; Email: sunjian8840@sina.com
  • Shandong
    • Qingdao, Shandong, China
      • Active, not recruiting
      • The Affiliated Hospital Of Qingdao University
  • Shanghai
    • Shanghai, Shanghai, China, 201508
      • Active, not recruiting
      • Shanghai Public Health Clinical Center
    • Shanghai, Shanghai, China
      • Recruiting
      • Renji Hospital, School of Medicine, Shanghai Jiao Tong University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

(I)Chinese Healthy Volunteers：In accordance with the criteria of each bioequivalence trial of NOACs；150-200 cases for each drug (II)Chinese Patients：In accordance with anticoagulation indications of NOACs，never received NOACs in a month and intend to take NOACs or have received NOACs for more than one week continuously；200 cases for each drug

Description

Inclusion Criteria:

(I)Chinese Healthy Volunteers

• In accordance with the inclusion criteria for each bioequivalence trial of NOACs;
• Sign informed consent of the research;
• Complete to collect indexes of pharmacodynamics and pharmacogenomics in the cycle with control drug.

(II)Chinese Patients

• In accordance with anticoagulation indications of NOACs, include prevention of thrombosis in non valvular atrial fibrillation, prevention and treatment of deep vein thrombosis / pulmonary embolism and prevention of thrombosis after knee / hip replacement;
• More than 18 years of age, male or female;
• Never received NOACs in a month and intend to take NOACs or have received NOACs for more than one week continuously;
• sign informed consent.

Exclusion Criteria:

(I)Chinese Healthy Volunteers

• In accordance with the exclusion criteria for each bioequivalence trial of NOACs;

(II)Chinese Patients

• With history of immunodeficiency disease, including positive HIV index;
• Positive Hepatitis B surface antigen (HBsAg) and HCV index;
• Combined therapy of CYP3A4 strong inhibitors and P-gp inhibitors (e.g., systemic pyrrole antifungal agents such as ketoconazole, itraconazole, voriconazole and posaconazole; human immunodeficiency virus (HIV) - protease inhibitors such as ritonavir), CYP3A4 strong inducers and P-gp inducers (e.g., rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's Wort, etc.) in 14 days before treatment with NOACs;
• Severe liver dysfunction and abnormal renal function;
• Include contraindications of NOACs, such as hypersensitivity, active bleeding, moderate or severe liver disease, previous history of intracranial hemorrhage, gastrointestinal hemorrhage in the past 6 months and major operation within 30 days.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
wild genotype; Through next generation sequencing, distinguish wild genotype of NOACs	Genetic: detection of genotype; detection of genotype by next generation sequencing
mutant genotype; Through next generation sequencing, distinguish mutant genotype of NOACs	Genetic: detection of genotype; detection of genotype by next generation sequencing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of stroke or systemic embolic events (including TIA)	During the observation time, record the incidence of stroke or systemic embolic events (including TIA) after NOACs(rivaroxaban, apixaban, dabigatran) administration by telephone or out-patient clinic.	At 1 year
Incidence of bleeding events	During the observation time, record the incidence of bleeding events after NOACs(rivaroxaban, apixaban, dabigatran) administration by telephone and out-patient clinic, including subcutaneous bleeding, gingival bleeding, gastrointestinal bleeding, intracranial hemorrhage, etc.	At 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genotype detected by next generation sequencing	Collect blood specimen before NOACs administration, then detect genotype of NOACs by next generation sequencing.	pre-dose of NOACs (rivaroxaban, apixaban, dabigatran)
Level of anticoagulant activity assessed by anti-factor Xa activity	Before and after rivaroxaban and apixaban administration, record anti-factor Xa activity detected by blood coagulation tests.	At baseline; at 3 hours, at 8 or 9 hours, at 12 hours for Chinese healthy volunteers, at 48 or 72 hours for Chinese patients
Level of anticoagulant activity assessed by anti-factor IIa activity	Before and after dabigatran administration, record anti-factor IIa activity detected by blood coagulation tests.	At baseline; at 2 hours, at 4 hours, at 8 hours, at 12 hours for Chinese healthy volunteers, at 72 hours for Chinese patients
Expression level of miRNA	Before and after NOACs administration, detect the expression level of miRNA about pharmacodynamics.	At baseline; at 2 or 3 hours, at 4 hours (only for dabigatran), at 8 or 9 hours, at 12 hours for Chinese healthy volunteers, at 48 or 72 hours for Chinese patients.
Expression level of LncRNA	Before and after NOACs administration, detect the expression level of LncRNA about pharmacodynamics.	At baseline; at 2 or 3 hours, at 4 hours (only for dabigatran), at 8 or 9 hours, at 12 hours for Chinese healthy volunteers, at 48 or 72 hours for Chinese patients.
Incidence of stroke or systemic embolic events in the other observation times	During the other observation time, record the incidence of stroke or systemic embolic events (including TIA) after NOACs(rivaroxaban, apixaban, dabigatran) administration by telephone or out-patient clinic.	At 1 month, 6 months and 2 years (according the actual duration of NOACs taken in patiens)
Incidence of bleeding events in the other observation times	During the other observation time, record the incidence of bleeding events after NOACs(rivaroxaban, apixaban, dabigatran) administration by telephone and out-patient clinic, including subcutaneous bleeding, gingival bleeding, gastrointestinal bleeding, intracranial hemorrhage, etc.	At 1 month, 6 months and 2 years (according the actual duration of NOACs taken in patiens)

Collaborators and Investigators

• Sponsor: Cui Yimin

Publications and helpful links

General Publications

• Liu Z, Mu G, Xie Q, Zhang H, Jiang J, Xiang Q, Cui Y. Hemoclot Thrombin Inhibitor Assay and Expected Peak-Trough Levels of Dabigatran: A Multicenter Study. Front Cardiovasc Med. 2022 Jul 22;9:894888. doi: 10.3389/fcvm.2022.894888. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 6, 2017
• Primary Completion (ANTICIPATED): October 1, 2021
• Study Completion (ANTICIPATED): December 1, 2021

Study Registration Dates

• First Submitted: May 9, 2017
• First Submitted That Met QC Criteria: May 18, 2017
• First Posted (ACTUAL): May 19, 2017

Study Record Updates

• Last Update Posted (ACTUAL): December 22, 2020
• Last Update Submitted That Met QC Criteria: December 19, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Other Study ID Numbers: 2016[1236]

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No