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Effect of age and gender on pharmacokinetics and pharmacodynamics of a single ticagrelor dose in healthy individuals

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study was to assess age and gender effects on ticagrelor pharmacokinetics and pharmacodynamics (PK/PD).

Methods

Forty healthy individuals [18–45 years (young); ≥65 years (elderly); ten men, ten women per age group) received 200 mg ticagrelor.

Results

Ticagrelor was rapidly absorbed [time to maximum concentration (Cmax) (tmax) 2.5–3.0 h], and its major active metabolite, AR-C124910XX rapidly formed (tmax 3.0–3.5 h) in all groups. Ticagrelor exposure was higher in elderly vs. the young [area under the curve from time 0 to infinity (AUC0-∞) 52%; Cmax 63% higher] and women vs. men (AUC0-∞ 37%; Cmax 52% higher). Mean terminal elimination half-life was slightly longer in women vs. men but was unaffected by age. Similar results were observed for AR-C124910XX (elderly vs. young, AUC0-∞ 48%; Cmax 61% higher), and in women vs. men (AUC0-∞ 55%; Cmax 56% higher). Across all groups, ticagrelor produced substantial final-extent inhibition of platelet aggregation (IPA): >90% at 4 and 8 h postdose. Individuals with highest ticagrelor exposure (i.e., elderly) had the lowest IPA, indicating an age-related platelet sensitivity effect. In young individuals, platelet sensitivity was greater in men vs. women. Ticagrelor tolerability was not affected by age or gender.

Conclusions

Systemic exposures to ticagrelor and AR-C124910XX were higher in elderly vs. young and in women vs. men. Age- and gender-related changes in IPA were apparent, but substantial IPA was achieved in all groups. No adjustment in ticagrelor dose should be considered necessary based on age and gender.

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References

  1. Husted S, van Giezen JJJ (2009) Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther 27:259–274

    Article  PubMed  CAS  Google Scholar 

  2. Brilique, summary of product characteristics, 2010. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001241/WC500100494.pdf Accessed 18 October 2011

  3. BrilintaTM, US full prescribing information, July 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022433s000lbl.pdf Accessed 10 October 2011

  4. James S, Åkerblom A, Cannon CP et al (2009) Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J 157:599–605

    Article  PubMed  CAS  Google Scholar 

  5. Wallentin L, Becker RC, Budaj A et al (2009) Ticagrelor vs. clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057

    Article  PubMed  CAS  Google Scholar 

  6. Teng R, Oliver S, Hayes MA, Butler K (2010) Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 38:1514–1521

    Article  PubMed  CAS  Google Scholar 

  7. Zhou D, Andersson TB, Grimm SW (2011) In vitro evaluation of potential drug-drug interactions with ticagrelor: cytochrome P450 reaction phenotyping, inhibition, induction and differential kinetics. Drug Metab Dispos 39:703–710

    Article  PubMed  CAS  Google Scholar 

  8. Ma Q, Lu AY (2011) Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev 63:437–459

    Article  PubMed  CAS  Google Scholar 

  9. McLean AJ, Le Couteur DG (2004) Aging biology and geriatric clinical pharmacology. Pharmacol Rev 56:163–184

    Article  PubMed  CAS  Google Scholar 

  10. Meibohm B, Beierle I, Derendorf H (2002) How important are gender differences in pharmacokinetics? Clin Pharmacokinet 41:329–342

    Article  PubMed  CAS  Google Scholar 

  11. Fromm MF (2003) Importance of P-glycoprotein for drug disposition in humans. Eur J Clin Invest 33(Suppl 2):6–9

    Article  PubMed  CAS  Google Scholar 

  12. Schuetz EG, Furuya KN, Schuetz JD (1995) Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 275:1011–1018

    PubMed  CAS  Google Scholar 

  13. Bebawy M, Chetty M (2009) Gender differences in P-glycoprotein expression and function: effects on drug disposition and outcome. Curr Drug Metab 10:322–328

    Article  PubMed  CAS  Google Scholar 

  14. Paine MF, Ludington SS, Chen M-L et al (2005) Do men and women differ in proximal small intestinal CYP3A or P-glyoprotein expression? Drug Metab Dispos 33:426–433

    Article  PubMed  CAS  Google Scholar 

  15. Klotz U (2009) Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev 41:67–76

    Article  PubMed  CAS  Google Scholar 

  16. Hilmer SN, Shenfield GM, Le Couteur DG (2005) Clinical implications of changes in hepatic drug metabolism in older people. Ther Clin Risk Manag 1:151–156

    Article  PubMed  CAS  Google Scholar 

  17. Cotreau MM, von Moltke LL, Greenblatt DJ (2005) The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet 44:33–60

    Article  PubMed  CAS  Google Scholar 

  18. Greenblatt DJ, von Moltke LL (2008) Gender has a small but statistically significant effect on clearance of CYP3A substrate drugs. J Clin Pharmacol 48:1350–1355

    Article  PubMed  CAS  Google Scholar 

  19. Scandlyn MJ, Stuart EC, Rosengren RJ (2008) Sex-specific differences in CYP450 isoforms in humans. Expert Opin Drug Metab Toxicol 4:413–424

    Article  PubMed  CAS  Google Scholar 

  20. He P, Court MH, Greenblatt DJ, von Moltke LL (2005) Genotype-phenotype associations of cytochrome P45 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin Pharmacol Ther 77:373–387

    Article  PubMed  CAS  Google Scholar 

  21. Butler K, Teng R (2010) Pharmacokinetics, pharmacodynamics and safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol 70:65–77

    Article  PubMed  CAS  Google Scholar 

  22. Teng R, Butler K (2010) Pharmacokinetics, pharmacodynamics, tolerability, and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 66:487–496

    Article  PubMed  CAS  Google Scholar 

  23. Regitz-Zagrosek V, Seeland U (2011) Sex and gender differences in myocardial hypertrophy and heart failure. Wein Med Wochenschr 161:109–116

    Article  Google Scholar 

  24. Boström G (2006) Chapter 9: habits of life and health. Scand J Pub Health 34(Suppl 67):199–228

    Article  Google Scholar 

  25. Bliden K, Dichiara J, Lawal L et al (2008) The association of cigarette smoking with enhanced platelet inhibition by clopidogrel. J Am Coll Cardiol 52:531–553

    Article  PubMed  CAS  Google Scholar 

  26. ICH harmonized tripartite guideline for good clinical practice E6(R1) (1996). Available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf Accessed 18 October 2011

  27. Sillén H, Cook M, Davis P (2010) Determination of ticagrelor and two metabolites in plasma samples by liquid chromatography and mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 878:2299–2306

    Article  PubMed  Google Scholar 

  28. Seber GAF, Wild CJ (2003) Unconstrained optimization. In: Seber GAF, Wild CJ (eds) Nonlinear regression. John Wiley & Sons, New Jersey, pp 587–618

    Google Scholar 

  29. Seber GAF, Wild CJ (2003) Computational method for nonlinear least squares. In: Seber GAF, Wild CJ (eds) Nonlinear regression. John Wiley & Sons, New Jersey, pp 619–660

    Google Scholar 

  30. Labarthe B, Théroux P, Angioï M, Ghitescu M (2005) Matching the evaluation of the clinical efficacy of clopidogrel to platelet function tests relevant to the biological properties of the drug. J Am Coll Cardiol 46:638–645

    Article  PubMed  CAS  Google Scholar 

  31. Mottino AD, Catania VA (2008) Hepatic drug transporters and nuclear receptors: regulation by therapeutic agents. World J Gastroenterol 14:7068–7074

    Article  PubMed  CAS  Google Scholar 

  32. Husted S, Emanuelsson H, Heptinstall S et al (2006) Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 27:1038–1047

    Article  PubMed  CAS  Google Scholar 

  33. Husted S, James S, Becker RC et al (2011) Ticagrelor versus. clopidogrel in elderly patients with acute coronary syndromes – a substudy from prospective randomized PLATelet inhibition and patient Outcomes (PLATO) trial. J Am Coll Cardiol 57(Suppl 1):e1099

    Article  Google Scholar 

  34. Karavidas A, Lazaros G, Tsiachris D, Pyrgakis V (2010) Aging and the cardiovascular system. Hellenic J Cardiol 51:421–427

    PubMed  Google Scholar 

  35. Löwenberg EC, Meijers JCM, Levi M (2010) Platelet-vessel wall interaction in health and disease. Neth J Med 68:242–251

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Thierry Duvauchelle and his team for conducting the study at ASTER, Paris, France. Staff at York Bioanalytical Solutions, York, UK, and Quest Pharmaceutical Services, Newark, DE, USA, are acknowledged for their hard work in the pharmacokinetic sample analyses within this study. We also thank Dr. Jackie Phillipson (Gardiner Caldwell Communications) who provided medical writing support funded by AstraZeneca.

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Authors and Affiliations

  1. Clinical Pharmacology, AstraZeneca LP, OW3-117, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE, 19850-5437, USA

    Renli Teng

  2. AstraZeneca Pharmaceuticals, Room C3B-316 1800 Concord Pike, P.O. Box 15437, Wilmington, DE, 19850-5437, USA

    Patrick Mitchell

  3. AstraZeneca Pharmaceuticals, B3B-704 A 1800 Concord Pike, P.O. Box 15437, Wilmington, DE, USA

    Kathleen Butler

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  1. Renli Teng
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Correspondence to Renli Teng.

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Teng, R., Mitchell, P. & Butler, K. Effect of age and gender on pharmacokinetics and pharmacodynamics of a single ticagrelor dose in healthy individuals. Eur J Clin Pharmacol 68, 1175–1182 (2012). https://doi.org/10.1007/s00228-012-1227-4

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  • DOI: https://doi.org/10.1007/s00228-012-1227-4

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