Impact of Biomarkers on Pharmacokinetics and Pharmacodynamics of Direct Oral Anticoagulants

Study Overview
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Brief Summary
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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.

Official Title
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Impact of Biomarkers on Pharmacokinetics and Pharmacodynamics of Direct Oral Anticoagulants

Conditions
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Novel Oral Anticoagulants, NOACs, Rivaroxaban, Apixaban, Dabigatran, Pharmacokinetics, Pharmacodynamics, Pharmacogenomics, Accurate Medication

Intervention / Treatment
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* Genetic: detection of genotype


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| wild genotype<br>Through next generation sequencing, distinguish wild genotype of NOACs | Genetic: detection of genotype<br>* detection of genotype by next generation sequencing<br>|
| mutant genotype<br>Through next generation sequencing, distinguish mutant genotype of NOACs | Genetic: detection of genotype<br>* detection of genotype by next generation sequencing<br>|

What is the study measuring?
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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) |