The Impact of Genotype on Pharmacokinetics and Antiplatelet Effects of Ticagrelor in Healthy Chinese

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: Ticagrelor

• Registration Number: NCT03092076
• Lead Sponsor: Guangdong Provincial People's Hospital

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).

Study Timeline

• Study Start: 2015-05-20
• Primary Completion: 2015-10-24
• Study Completion: 2016-06-16
• Status Verified: 2017-03
• Study First Submitted: 2017-03-09
• Study First Submitted QC: 2017-03-21
• Last Update Submitted: 2017-03-21
• Study First Posted: 2017-03-27
• Last Update Posted: 2017-03-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 51

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Antiplatelet effects	Ticagrelor	The antiplatelet effects of ticagrelor in healthy Chinese is investigated to provide the basis for its efficacy and safety of clinical treatment.
Pharmacokinetics	Ticagrelor	The pharmacokinetics characteristic of ticagrelor in healthy Chinese is investigated to provide the basis for its efficacy and safety of clinical treatment.

Primary Outcome Measures

Name	Time	Method
Genome-wide genotyping in 51 healthy Chinese	10 weeks	A total of 900,015 SNPs in a GWAS scan were genotyped with the Illumina HumanOmniZhongHua-8 BeadChip according to the protocol from Illumina. Prior to association analysis, a systematic quality control (QC) procedure was applied to the raw genotyping data to filter unqualified SNPs and samples. The effects of genetic variants on antiplatelet and pharmacokinetic response to ticagrelor are investigated through a genome-wide association study（GWAS）in 51 healthy Chinese .

Secondary Outcome Measures

Name	Time	Method
ADP-stimulated platelet aggregation	8 weeks	For platelet function tests, ADP-stimulated platelet aggregation was measured in ethylenediaminetetraacetic acid (EDTA) anticoagulated whole blood samples (2 x 2 mL) within 2 h of sampling using a Chrono-log Platelet Aggregation Systems. The platelet aggregation (PA) postdose till recovery to baseline was measured by light transmission method using ADP (20 μmol/L final concentration), and expressed as percentages. Since a sparse sampling design for platelet function testing was used, the missing platelet aggregation data during the recovery of platelet function were imputed using Bayesian simulation method. The time recovering 50% of maximum drug effect (RT50) were estimated individually, which were used to represent the antiplatelet effect.
Peak plasma concentration (Cmax)	10 weeks	A LC-MS/MS assay was developed and validated for simultaneous determination of ticagrelor, its metabolites, and internal standard (ferulic acid) in human plasma. Plasma samples were extracted with ethyl acetate. Peak plasma concentration (Cmax) of ticagrelor and M8 were estimated for each subject, using the non-compartmental analysis function in Phoenix WinNonlin software, version 6.3.
Time to peak plasma concentration (tmax)	10 weeks	A LC-MS/MS assay was developed and validated for simultaneous determination of ticagrelor, its metabolites, and internal standard (ferulic acid) in human plasma. Plasma samples were extracted with ethyl acetate. Time to peak plasma concentration (tmax) of ticagrelor and M8 were estimated for each subject, using the non-compartmental analysis function in Phoenix WinNonlin software, version 6.3.
Area under the plasma concentration-time curve (AUC)	10 weeks	A LC-MS/MS assay was developed and validated for simultaneous determination of ticagrelor, its metabolites, and internal standard (ferulic acid) in human plasma. Plasma samples were extracted with ethyl acetate. Area under the plasma concentration-time curve (AUC) of ticagrelor and M8 were estimated for each subject, using the non-compartmental analysis function in Phoenix WinNonlin software, version 6.3.
Accumulated amount of ticagrelor and its metabolites in urine	10 weeks	A LC-MS/MS assay was developed and validated for simultaneous determination of ticagrelor, its metabolites, and internal standard (gliclazide) in human urine. Urine samples were precipitated with 50% methanol/acetonitrile. Accumulated amount of ticagrelor and its metabolites in urine over 24 h was calculated. The relative accumulated amount was the product of the relative index and the urine volume (Compound/IS x Vurine).