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Integrated Pharmacokinetics/Pharmacodynamics Model and Simulation of the Ticagrelor Effect on Patients with Acute Coronary Syndrome

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Abstract

Background

Data available for pharmacokinetics (PK)/pharmacodynamics (PD) of ticagrelor and significant endogenous/exogenous factors or biomarkers related to bleeding events in both healthy and clinical patients are limited.

Objective

Based on PK and PD data from multicenter healthy subjects and patients, we aimed to establish an integrated approach towards population PK (pop PK) and the PD model of ticagrelor.

Methods

This study was conducted as a multicenter, prospective clinical registration study involving both healthy subjects and clinical patients. The integrated Pharmacokinetic/pharmacodynamic (PK/PD) models were characterized based on PK/PD [ticagrelor concentration, aggregation baseline (BASE), P2Y12 response unit (PRU) and inhibition rate (INHIBIT)] data from 175 healthy volunteers. The model was corrected by sparse PD (BASE, PRU and INHIBIT) data from 208 patients with acute coronary syndrome (ACS). The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored.

Results

A one-compartment, linear model with first-order absorption was adopted as PK model. Food status (FOOD) and body weight (WT) significantly influenced clearance and improved the fitting degree of the PK model, while SEX was selected as the covariates of the PD model. For patients taking ticagrelor 90 mg, the peak value [mean (95% CI)] of PRU was 355.15 (344.24–366.06) and the trough value was 3.64 (3.14–4.15). The PRU mean parameters were basically within the expected range (80–200) of the literature suggestions.

Conclusion

A fixed dose of ticagrelor, without adjusting the dosing regimen other than covariates of FOOD/WT/SEX, could be used in patients with acute coronary syndromes, and the standard regimen could be used in Chinese patients from the perspective of exposure.

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Author information

Author notes

  1. Zhiyan Liu and Yaou Liu contributed equally.

Authors and Affiliations

  1. Department of Pharmacy, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China

    Zhiyan Liu, Yaou Liu, Guangyan Mu, Hanxu Zhang, Shuang Zhou, Zhe Wang, Qiufen Xie, Zining Wang, Qian Xiang & Yimin Cui

  2. School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China

    Guangyan Mu, Hanxu Zhang, Shuang Zhou, Zhe Wang, Qiufen Xie, Zining Wang, Qian Xiang & Yimin Cui

  3. Center of Clinical Pharmacology, The Second Affiliated Hospital of Nanchang University, Jiangxi, China

    Ninghong Guo & Jian Li

  4. Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Hunan, China

    Jie Huang & Guoping Yang

  5. Department of Pharmacy, Zhengzhou Seventh People’s Hospital, Zhengzhou, China

    Liping Guo & Dongdong Yuan

  6. Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Anhui, China

    Yan Huang

  7. Department of Pharmacy, 900 Hospital of the Joint Logistics Team, Fuzhou, China

    Hongtao Song

  8. Department of Cardiology, Peking University First Hospital, Beijing, China

    Jie Jiang

  9. Institute of Clinical Pharmacology, Peking University, Beijing, China

    Yimin Cui

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  1. Zhiyan Liu
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Corresponding authors

Correspondence to Qian Xiang or Yimin Cui.

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Funding

This study was supported by grants from the National High-Level Hospital Clinical Research Funding (Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital, 2022CX04 and 2022CX14), Capital’s Funds for Health Improvement and Research (2022-2Z-40712), the National Key R&D Program of China (2016YFC0904900), and National Natural Science Foundation of China (81872940, 81973395 and 82073935).

Conflict of interest/competing interest

Zhiyan Liu, Yaou Liu, Guangyan Mu, Hanxu Zhang, Shuang Zhou, Zhe Wang, Qiufen Xie, Zining Wang, Ninghong Guo, Jie Huang, Liping Guo, Yan Huang, Jian Li, Guoping Yang, Dongdong Yuan, Hongtao Song, Jie Jiang, Qian Xiang, and Yimin Cui declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript.

Ethics approval

This study was approved by an independent ethics committee and the Institutional Review Board of Peking University First Hospital and all the participating subcentral hospitals.

Consent to participate

All involved subjects were briefed on the study and provided written informed consent.

Data availability statement

All data related to the study are shown in the article and supplementary materials. For access to other relevant data, contact the authors.

Author contributions

YMC and QX designed the research; ZYL, GYM, HXZ, NHG, JH, JJ, JL, DDY, YH, HTS and GPY performed experiments and collected data; YOL, SZ, ZW, QFX, and ZNW analyzed the data; ZYL and YOL wrote the manuscript. All authors have read and approved the final manuscript.

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Not applicable.

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Supplementary Information

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Supplementary file1 (DOCX 485 KB)

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Liu, Z., Liu, Y., Mu, G. et al. Integrated Pharmacokinetics/Pharmacodynamics Model and Simulation of the Ticagrelor Effect on Patients with Acute Coronary Syndrome. Clin Pharmacokinet 62, 435–447 (2023). https://doi.org/10.1007/s40262-022-01208-0

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  • DOI: https://doi.org/10.1007/s40262-022-01208-0

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