Pharmacokinetics, Bioequivalence and Safety Evaluation of Two Ticagrelor Tablets Under Fasting and Fed Conditions in Healthy Chinese Subjects

Abstract

Purpose

To evaluate the pharmacokinetics (PK), bioequivalence and safety profiles of test drug and reference drug of 90 mg ticagrelor tablets and their main active metabolite AR-C124910XX under fasting and fed conditions.

Methods

This was a randomized, open-label, single-dose, two-period, two-sequence, and two-treatment crossover study. Subjects were randomized and evenly administered with a single dose of test drug or reference drug of 90 mg ticagrelor tablets orally under fasting or fed conditions with a 7-day washout period. The primary PK parameters were calculated with non-compartmental model, including peak concentration (C_max), area under the curve (AUC) from zero to last quantifiable concentration (AUC_0-t), and AUC from zero to infinity (AUC_0-∞). Bioequivalence was judged by whether the 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of the test/reference drugs were within the predefined range of 80–125%. Adverse events (AEs) were assessed as safety endpoints.

Results

Eighty healthy Chinese subjects (fasting condition: n=40; fed condition: n=40) were enrolled, but two withdrew for personal reasons. As for PK parameters, there was no statistical difference (P>0.05) between the test and reference drugs under both conditions. As for bioequivalence, the 90% CIs of GMR for C_max, AUC_0-t and AUC_0-∞ all fell within 80%-125% regardless of food intake or not. No severe adverse events were observed in the study. Chinese clinical trial registration number is ChiCTR1800015091 (http://www.chictr.org.cn).

Conclusion

Our results demonstrated that the test drug and the reference drug of ticagrelor tablets were bioequivalent. The PK and safety profiles were also similar regardless of food intake or not in healthy Chinese subjects.

Keywords:

• ticagrelor
• bioequivalence
• pharmacokinetics
• safety

Acknowledgment

All authors sincerely acknowledge the subjects who were enrolled for their contributions to the clinical trial.

Abbreviations

PK, pharmacokinetics; C_max, peak concentration; AUC, area under the curve; AUC_0–t, AUC from zero to last quantifiable concentration; AUC_0–∞, AUC from zero to infinity; CIs, confidence intervals; GMR, geometric mean ratio; AEs, adverse events; ACS, acute coronary syndromes; DAPT, dual antiplatelet therapy; ACCF/AHA, American College of Cardiology Foundation/American Heart Association; CYP450, cytochrome P450 enzymes; FDA, United States Food and Drug Administration; IPA, inhibition of platelet aggregation; T, test drug; R, reference drug; BMI, body mass index; ECG, electrocardiogram; IEC, Independent Ethics Committee; PLA, People’s Liberation Army; GCP, the Guidelines of Good Clinical Practice; ICF, informed consent forms; T-R, Test-Reference; R-T, Reference-Test; LC-MS/MS, liquid chromatography-tandem mass spectrometry; QC, quality controls; LQC, low-quality control; GMQC, geometric mean-quality control; MQC, middle-quality control; HQC, high-quality control; λ_z, rate constant of apparent terminal elimination; t_1/2, terminal elimination half-life; T_max, time to Cmax; F, relative bioavailability; SOC, System Organ Class; PT, Preferred Term; CTCAE, Common Terminology Criteria for Adverse Events; FAS, full analysis set; SS, safety set; PKCS, pharmacokinetic analysis concentration set; PKPS, pharmacokinetic analysis parameter set; BES, bioequivalence analysis set; %CV, coefficient of variation; ANOVA, analysis of variance.

Date Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethics Approval and Informed Consent

The clinical trial was approved by the Independent Ethics Committee of People’s Liberation Army General Hospital (C2017-061-03). The study was conducted in accordance with the Declaration of Helsinki (1989), the Guidelines of Good Clinical Practice and local applicable laws and regulations. All subjects have provided written informed consent forms prior to their participation in the study.

Consent for Publication

All named authors take responsibility for the integrity of the work as a whole and have given their approval for this version to be published.

Disclosure

The authors declare that there are no conflicts of interest.

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.