Impact of Biomarkers on Pharmacokinetics and Pharmacodynamics of Ticagrelor

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%. Ticagrelor is a new-type receptor antagonist of P2Y12 and it is not affected by the influence of CYP2C19 polymorphism. With lack of predicted biomarkers, especially the research data of Chinese, it has the important significance in studying individual differences of ticagrelor in the antiplatelet 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 ticagrelor and provide scientific basis for accurate medication guide for people to use ticagrelor.

Official Title
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Impact of Biomarkers on Pharmacokinetics and Pharmacodynamics of Ticagrelor

Conditions
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Ticagrelor, 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 ticagrelor; Sign informed consent of the research; Complete to collect indexes of pharmacodynamics and pharmacogenomics in the cycle with control drug. (II)Chinese Patients With diagnosis of acute coronary syndrome (ACS), included unstable angina, non ST segment elevation myocardial infarction and ST segment elevation myocardial infarction; More than 18 years of age, male or female; Never received ticagrelor in a month and intend to take ticagrelor or have received ticagrelor 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 ticagrelor; (II)Chinese Patients With history of immunodeficiency disease, including positive HIV index; Positive Hepatitis B surface antigen (HBsAg) and HCV index; Combined therapy of CYP3A potent inhibitors (e.g., ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, Atazanavir, etc.), CYP3A substrate of narrow therapy window (e.g., cyclosporine, quinidine, etc.) and potent inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine, etc.) in 14 days before treatment with ticagrelor; Severe liver dysfunction and abnormal renal function; Uncontrolled hypertension, or systolic blood pressure > 180mmHg or diastolic pressure > 110mmHg during screening; Include contraindications of ticagrelor, 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 ticagrelor | Genetic: detection of genotype<br>* detection of genotype by next generation sequencing<br>|
| mutant genotype<br>Through next generation sequencing, distinguish mutant genotype of ticagrelor | 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 major adverse cardiac events (MACE) | During the observation time, record the incidence of MACE after ticagrelor administration by telephone or outpatient clinic , including myocardial infarction, cardiac death, stent stenosis, stent thrombosis, ect. | At 1 year | 
| Incidence of bleeding events | During the observation time, record the incidence of bleeding events after ticagrelor administration by telephone or outpatient 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 ticagrelor administration, then detect genotype of Ticagrelor by next generation sequencing. | pre-dose of Ticagrelor | 
| Level of platelet reactivity assessed by ADP aggregation rate | Before and after ticagrelor administration, record the ADP aggregation rate detected by Light Transmittance Aggregometry(LTA). | At baseline, at 12 hours for Chinese healthy volunteers or at 48 hours for Chinese patients. | 
| Level of platelet reactivity assessed by PRI | Before and after ticagrelor administration, record PRI detected by VerifyNow System. | At baseline, at 12 hours for Chinese healthy volunteers or at 48 hours for Chinese patients. | 
| Expression level of miRNA | Before and after ticagrelor administration, detect the expression level of miRNA about pharmacodynamics. | At baseline, at 12 hours for Chinese healthy volunteers or at 48 hours for Chinese patients. | 
| Expression level of proteomics | Before and after ticagrelor administration, detect the expression level of proteomics about pharmacodynamics | At baseline, at 12 hours for Chinese healthy volunteers or at 48 hours for Chinese patients | 
| Expression level of LncRNA | Before and after ticagrelor administration, detect the expression level of LncRNA about pharmacodynamics. | At baseline, at 12 hours for Chinese healthy volunteers；at 48 hours for Chinese patients. | 
| Incidence of MACEs in the other observation times | During the other observation time, record the incidence of MACE after ticagrelor administration by telephone or outpatient clinic , including myocardial infarction, cardiac death, stent stenosis, stent thrombosis, ect. | At 1 month, 6 months and 2 years (according the actual duration of ticagrelor taken in patiens) | 
| Incidence of bleeding events in the other observation times | During the other observation time, record the incidence of bleeding events after ticagrelor administration by telephone or outpatient clinic, including subcutaneous bleeding, gingival bleeding, gastrointestinal bleeding, intracranial hemorrhage, etc. | At 1 month, 6 months and 2 years (according the actual duration of ticagrelor taken in patiens) |