Impact of Biomarkers on Pharmacokinetics and Pharmacodynamics of Ticagrelor

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.

Study Overview

• Status: Unknown
• Conditions: Pharmacokinetics; Pharmacodynamics; Pharmacogenomics; Accurate Medication; Ticagrelor
• Intervention / Treatment: Genetic: detection of genotype

• Study Type: Observational
• Enrollment (Anticipated): 400

Contacts and Locations

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China, 230001
      • Recruiting
      • Anhui Provincial Hospital（The First Affiliated Hospital Of USTC）
    • Hefei, Anhui, China, 230001
      • Recruiting
      • The First Affiliated Hospital of Anhui Medical University
      • Contact: Yan Huang, MS; Phone Number: +86-15056922343; Email: hyayd123@126.com
  • Beijing
    • Beijing, Beijing, China, 100034
      • Recruiting
      • Peking University First Hospital
  • Fujian
    • Fuzhou, Fujian, China
      • Recruiting
      • 900 Hospital of the Joint Logistics Team (Original name: Fuzhou General Hospital of Nanjing Militray Command)
  • Henan
    • Zhengzhou, Henan, China, 450006
      • Active, not recruiting
      • The 7th People's Hospital of Zhengzhou
  • Hunan
    • Changsha, Hunan, China
      • Active, not recruiting
      • The Third Xiangya Hospital of Central South University
  • Jiangxi
    • Nanchang, Jiangxi, China, 330006
      • Active, not recruiting
      • The Second Affiliated Hospital of Nanchang 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 ticagrelor；150-200 cases (II)Chinese Patients：With diagnosis of acute coronary syndrome (ACS)，never received ticagrelor in a month and intend to take ticagrelor or have received ticagrelor for more than one week continuously；200 cases

Description

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.

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 ticagrelor	Genetic: detection of genotype; detection of genotype by next generation sequencing
mutant genotype; Through next generation sequencing, distinguish mutant genotype of ticagrelor	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 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)

Collaborators and Investigators

• Sponsor: Cui Yimin

Publications and helpful links

General Publications

• Xiang Q, Liu Z, Mu G, Xie Q, Zhang H, Zhou S, Wang Z, Guo N, Huang J, Jiang J, Li J, Yang G, Cui Y. Effect of Genetic Polymorphism Including NUP153 and SVEP1 on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects. Clin Drug Investig. 2022 May;42(5):447-458. doi: 10.1007/s40261-022-01154-6. Epub 2022 Apr 30.
• Yuan D, Shi X, Gao L, Wan G, Zhang H, Yang Y, Zhao Y, Sun D. Identification of Potential Biological Factors Affecting the Treatment of Ticagrelor After Percutaneous Coronary Intervention in the Chinese Population. Pharmgenomics Pers Med. 2022 Jan 20;15:29-43. doi: 10.2147/PGPM.S338287. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 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[1235]

Drug and device information, study documents

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