Therapeutic Drug Monitoring of Ticagrelor in Jordanian Patients. Development of Physiologically-Based Pharmacokinetic (PBPK) Model and Validation of Class IV Drugs of Salivary Excretion Classification System (SECS).

Year 2022, Volume: 26 Issue: 5, 1411 - 1419, 28.06.2025

Mohammed Khalil Akram Al-saleh Hana Makhamreh Rabab Tayem Mohammad Abufarah Abdullah Zubi Omaimah Najib Mohammad Bader Naji Najib Suliman Alfayoumi Nasir Idkaidek

Abstract

Ticagrelor is an orally administered antiplatelet agent that has been approved for the reduction of
cardiovascular risk in patients with history of cardiovascular disease. However, Ticagrelor can also cause adverse
effects, including dyspnea. Ticagrelor plasma and saliva concentrations of 63 Jordanian patients were measured using
a sensitive LCMS/MS method. Ticagrelor was not excreted in saliva as it corresponds to the Class IV salivary excretion
classification system. The correlation between plasma ticagrelor concentrations and the occurrence of dyspnea was
examined to establish a therapeutic window for plasma ticagrelor. A physiologically-based pharmacokinetic (PBPK)
model of ticagrelor was built and validated using previously- published plasma data. The validated model was then
used to predict the factors affecting ticagrelor plasma concentrations. A loading dose of 135 mg (1.5 tablet) instead of 2
tablets has been suggested to maintain its therapeutic effect and avoid dyspnea.

Keywords

Ticagrelor , pharmacokinetics , SECS , TDM , Gastroplus , PBPK

References

• [1] Whalan. Lippincott® Illustrated Reviews: Pharmacology. South Asian Edition ed, India, 2002, pp.396–400
• [2] Highlights of Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022433s020lbl.pdf
• [3] Ticagrelor Monograph for Professionals. https://www.drugs.com/monograph/ticagrelor.html#uses
• [4] RenliTeng, et al. Pharmacokinetic Profiles of Ticagrelor Orodispersible Tabletsin Healthy Western and Japanese Subjects. Clin Drug Investig. 2017, 37:1035–1045 [Crossref]
• [5] Idkaidek, N. and Arafat, T. Saliva versus plasma pharmacokinetics: Theory and application of a salivary excretion classification system. Molecular Pharmaceutics, 2012, 9(8), pp. 2358–2363. [Crossref]
• [6] Parkway, NuventraPharma Sciences2525 Meridian, and Suite 200 Durham. “What Is PBPK Modeling & Simulation in Drug Development?” PK / PD and Clinical Pharmacology Consultants, 9 Sept. 2020. https://www.nuventra.com/resources/blog/what-is-pbpk-modeling-simulation/
• [7] Nestorov . Whole-body physiologically based pharmacokineticmodels. Expert Opinion on Drug Metabolism & Toxicology 2007; 3 (2):235–249 [Crossref]
• [8] https://www.Scifinder.com
• [9] BrilintaTM (ticagrelor) Tablets. (2012). Pharmacy and Therapeutics, 37(4 section 2), pp.4–18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353491/
• [10] Butler K, Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J ClinPharmacol. 2010;70:65–77 [Crossref]
• [11] https://pubchem.ncbi.nlm.nih.gov/compound/Ticagrelor
• [12] Adamski, P., Buszko, K., Sikora, J., Niezgoda, P., Barańska, M., Ostrowska, M., Paciorek, P., Navarese, E.P., Gorog, D.A. and Kubica, J. Metabolism of ticagrelor in patients with acute coronary syndromes. Scientific Reports, 2018, 8(1) [Crossref]
• [13] Krakowiak, Alicja, et al. Ticagrelor-Related Severe Dyspnoea: Mechanisms, Characteristic Features, Differential Diagnosis and Treatment. Clinical Medicine Insights: Case Reports, vol. 13, Jan. 2020. [Crossref]
• [14] Renli Teng. Ticagrelor: Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Profile: An Update. Clinical Pharmacokinetics,2015, vol. 54, no. 11,pp. 1125–1138 [Crossref]
• [15] Bioanalytical Method Validation Guidance for Industry. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM) May 2018. https://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf