Clinical trial NCT03092076: The Impact of Genotype on Pharmacokinetics and Antiplatelet Effects of Ticagrelor in Healthy Chinese
Official title: The Impact of Genotype on Pharmacokinetics and Antiplatelet Effects of Ticagrelor in Healthy Chinese
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: pharmacokinetics
antiplatelet effects
single nucleotide polymorphism (SNP)
Lead sponsor: Guangdong Provincial People's Hospital
Sponsor class: OTHER
First posted: 2017-03-27
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This study is a open and single center clinical trial in healthy Chinese.The objective of the study is to clarify the pharmacokinetics characteristics and antiplatelet effects of ticagrelor in Chinese and to investigate the impact of genotype.

Detailed description: This is an open-label, single-does, nonrandomized study of ticagrelor in healthy volunteers carried out at a single center. Written informed consent will be obtained from all volunteers before initiation of the study. The study is approved by the Research Ethic Committee of Guangdong General Hospital. Fifty-one healthy Chinese will be recruited.

Venous blood will be collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48h after taking 180mg ticagrelor orally. Urine collection intervals are at predose and 0 to 2, 2 to 4, 4 to 6, 6 to 9, 9 to 12, 12 to 16 and 16 to 24h after dosing. The concentration of ticagrelor and its metabolites will be analyzed using a separately validated liquid chromatography technique with tandem mass spectrometric detection (LC-MS/MS).

Besides，the basic principle of population pharmacodynamics(PPD) is applied to evaluate antiplatelet effects. Adenosine diphosphate(ADP)-stimulated platelet aggregation will be assessed at baseline, and 0.5h/1h, 2h, 4h/8h/24h, 48h/3d/5d and 7d after dosing.

The effects of genetic variants on antiplatelet and pharmacokinetic response to ticagrelor are investigated through a genome-wide association study (GWAS).

Eligibility criteria: Inclusion Criteria:

1. Age: 18 - 45 years;
2. Sex: male and female;
3. Ethnicity: Chinese;
4. Good health as evidenced by the results of physical examination, vitals signs, electrocardiogram, and clinical laboratory test results, but there were exceptions if an abnormal value was considered not to be clinical significance;
5. Written informed consent.

Exclusion Criteria:

1. Any conditions known to interfere with the absorption, distribution, metabolism or excretion of drugs;
2. Intolerance or hypersensitivity to drugs whose mechanism is similar to that of ticagrelor;
3. Any history of taking medicines within half a month before enrollment;
4. Any history of whole blood transfusion within 2 months, blood elements transfusion or blood donation within 1 months before enrollment;
5. Participation in a clinical study within 3 months before enrollment;
6. Abuse of caffeine (\> 5 units/day), alcohol(\> 21 units /week), smoking(\> 10 cigarettes/day);
7. Positive serology for Hbs antigen and HIV;
8. History of coagulation disorders.

Primary outcomes:
measure: Genome-wide genotyping in 51 healthy Chinese
timeFrame: 10 weeks
Secondary outcomes:
measure: ADP-stimulated platelet aggregation
timeFrame: 8 weeks
measure: Peak plasma concentration (Cmax)
timeFrame: 10 weeks
measure: Time to peak plasma concentration (tmax)
timeFrame: 10 weeks
measure: Area under the plasma concentration-time curve (AUC)
timeFrame: 10 weeks
measure: Accumulated amount of ticagrelor and its metabolites in urine
timeFrame: 10 weeks
Other outcomes:
Locations:
Study officials:
affiliation: Guangdong Provincial People's Hospital
name: Shilong Zhong, Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Xu G, Liu JE, Liu X, Zhong W, Wang Z, Li H, Xiao X, Chen J, Zhong S, Lai W. DNA methylation mediates the genetic variants on ticagrelor major metabolite elimination and platelet function recovery after ticagrelor discontinuation. Epigenomics. 2022 May;14(10):601-613. doi: 10.2217/epi-2021-0461. Epub 2022 May 16.
citation: Zhu Q, Zhong W, Wang X, Mai L, He G, Chen J, Tang L, Liu S, Lai W, Zhong S. Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects. Front Pharmacol. 2019 Mar 18;10:209. doi: 10.3389/fphar.2019.00209. eCollection 2019.