Skip to main content
SpringerLink
Log in

Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers

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

Abstract

Purpose

Interactions between ticagrelor and atorvastatin or simvastatin were investigated in two-way crossover studies.

Methods

Both studies were open-label for statin; the atorvastatin study was placebo-controlled for ticagrelor. For atorvastatin, volunteers (n = 24) received ticagrelor (loading dose 270 mg; 90 mg twice daily, 7 days) or placebo, plus atorvastatin calcium (80 mg; day 5). For simvastatin, volunteers (n = 24) received simvastatin 80 mg, or ticagrelor (loading dose 270 mg; 180 mg twice daily, 7 days) plus simvastatin (80 mg; day 5). In each study, volunteers received the alternate treatment after washout (≥7 days).

Results

Ticagrelor increased mean atorvastatin maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from zero to infinity (AUC) by 23 % and 36 %, respectively. Simvastatin Cmax and AUC were increased by 81 % and 56 % with ticagrelor. Ticagrelor also increased Cmax and AUC of analysed atorvastatin metabolites by 13–55 % and 32–67 %, respectively, and simvastatin acid by 64 % and 52 %, respectively. Co-administration of ticagrelor with each statin was well tolerated.

Conclusions

Exposure to ticagrelor and its active metabolite, AR-C124910XX, was generally unchanged by a single dose of either statin, except for a minor increase in ticagrelor Cmax in the presence of simvastatin. Effects of ticagrelor on atorvastatin pharmacokinetics were modest and unlikely clinically relevant, while with simvastatin, changes were slightly larger, and simvastatin doses >40 mg with ticagrelor should be avoided.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, Wickens M, Emanuelsson H, Gurbel P, Grande P, Cannon CP (2007) Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol 50:1852–1856

    Article  PubMed  CAS  Google Scholar 

  2. Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, Storey RF, DISPERSE-2 Investigators (2007) Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral ADP receptor antagonist, compared with clopidogrel, in patients with non–ST segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol 50:1844–1851

    Article  PubMed  CAS  Google Scholar 

  3. 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 

  4. van Giezen JJJ, Berntsson P (2008) AZD6140 displays over 100-fold higher affinity for the P2Y12 receptor vs AZ11702105, a chemical compound indistinguishable from the active metabolite of prasugrel, and is a more potent inhibitor of ADP-induced platelet aggregation. Arterioscler Thromb Vasc Biol 28:e139–e140

    Google Scholar 

  5. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, For the Harrington RA for the PLATO Investigators (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057

    Article  PubMed  CAS  Google Scholar 

  6. Brilique, summary of product characteristics (2010) http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001241/WC500100494.pdf. Accessed 8 November 2011

  7. BrilintaTM, US full prescribing information (July 2011) http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022433s000lbl.pdf. Accessed 8 November 2011

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

    Article  PubMed  CAS  Google Scholar 

  9. Teng R, Butler K (2008) AZD6140, The first reversible oral platelet P2Y12 receptor antagonist, has linear pharmacokinetics and provides near complete inhibition of platelet aggregation, with reversibility of effect in healthy subjects. Can J Clin Pharmacol 15:e426

    Google Scholar 

  10. Teng R, Butler K (2010) Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 66:487–496

    Article  PubMed  CAS  Google Scholar 

  11. Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G (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 

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

    Article  PubMed  CAS  Google Scholar 

  13. 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 

  14. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC Jr, Jacobs AK, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B (2007) ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction. Circulation 116:e148–304

    Article  PubMed  Google Scholar 

  15. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology, Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernández-Avilés F, Fox KA, Hasdai D, Ohman EM, Wallentin L, Wijns W (2007) Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 28:1598–1660

    Article  PubMed  CAS  Google Scholar 

  16. Scandinavian Simvastatin Survival Study Group (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4 S). Lancet 344:1383–1389

    Google Scholar 

  17. LaRosa JC, He J, Vupputuri S (1999) Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. J Am Med Assoc 282:2340–2346

    Article  CAS  Google Scholar 

  18. Cannon CP, Braunwauld E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM (2004) Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350:1495–1504

    Article  PubMed  CAS  Google Scholar 

  19. Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, Zeiher A, Chaitman BR, Leslie S, Stern T, For the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators (2001) Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study; a randomized controlled trial. J Am Med Assoc 285:1711–1718

    Article  CAS  Google Scholar 

  20. Aronow HD, Topol EJ, Roe MT, Houghtaling PL, Wolski KE, Lincoff AM, Harrington RA, Califf RM, Ohman EM, Kleiman NS, Keltai M, Wilcox RG, Vahanian A, Armstrong PW, Lauer MS (2001) Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study. Lancet 357:1063–1068

    Article  PubMed  CAS  Google Scholar 

  21. LipitorTM, summary of product characteristics (September 2011) http://www.medicines.org.uk/EMC/medicine/1424/SPC/Lipitor+10mg%2c+20mg%2c+40mg%2c+80mg+Tablets/. Accessed 8 November 2011

  22. Zocor®, summary of product characteristics (March 2011). http://www.medicines.org.uk/EMC/medicine/1201/SPC/Zocor+10mg%2c+20mg%2c+40mg++and+80mg+film-coated+tablets/. Accessed 4 October 2011

  23. Lennernäs H (2003) Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 42:1141–1160

    Article  PubMed  Google Scholar 

  24. Prueksaritanont T, Gorham LM, Ma B, Liu L, Yu X, Zhao JJ, Slaughter DE, Arison BH, Vyas KP (1997) In vitro metabolism of simvastatin in humans: identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos 25:1191–1199

    PubMed  CAS  Google Scholar 

  25. Park JE, Kim KB, Bae SK, Moon BS, Liu KH, Shin JG (2008) Contribution of cytochrome P450 3A4 and 3A5 to the metabolism of atorvastatin. Xenobiotica 38(9):1240–1251

    Article  PubMed  CAS  Google Scholar 

  26. Lilja JJ, Kivistö KT, Neuvonen PJ (1999) Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 66:118–127

    PubMed  CAS  Google Scholar 

  27. Lilja JJ, Kivisto KT, Neuvonen PJ (1998) Grapefruit juice-simvastatin interaction: effects on serum concentration of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 64:477–483

    Article  PubMed  CAS  Google Scholar 

  28. 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 Sci 878:2299–2306

    Article  Google Scholar 

  29. Bhindi R, Ormerod O, Newton J, Banning AP, Testa L (2008) Interaction between statins and clopidogrel: is there anything clinically relevant? Q J Med 101:915–925

    Article  CAS  Google Scholar 

  30. Bottorff MB (2006) Statin safety and drug interactions: clinical implications. Am J Cardiol 97(Suppl):27C–31C

    Article  PubMed  CAS  Google Scholar 

  31. Bellosta S, Paoletti R, Corsini A (2004) Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation 109(Suppl III):50–57, III

    Google Scholar 

  32. Jacobson TA (2004) Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 94:1140–1146

    Article  PubMed  CAS  Google Scholar 

  33. Shitara Y, Sugiyama Y (2006) Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther 112:71–105

    Article  PubMed  CAS  Google Scholar 

  34. FDA Guidance for Industry (2012) Drug interaction studies – study design, data analysis, and implications for dosing and labelling recommendations. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf. Accessed 24 April 2012

  35. Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M (2006) SLCO1B1 Polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 16:873–879

    Article  PubMed  CAS  Google Scholar 

  36. Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M (2007) Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther 82:726–733

    Article  PubMed  CAS  Google Scholar 

  37. Gibson DM, Bron NJ, Richens A, Hounslow NJ, Sedman AJ, Whitfield LR (1996) Effect of age and gender on pharmacokinetics of atorvastatin in humans. J Clin Pharmacol 36:242–246

    PubMed  CAS  Google Scholar 

  38. Narwal R, Akhlaghi F, Asberg A, Hermann M, Rosenbaum SE (2010) Development of a population pharmacokinetic model for atorvastatin acid and its lactone metabolite. Clin Pharmacokinet 49:693–702

    Article  PubMed  CAS  Google Scholar 

  39. Keskitalo JE, Kurkinen KJ, Neuvoneni PJ, Niemi M (2008) ABCB1 Haplotypes differentially affect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin. Clin Pharmacol Ther 84:457–461

    Article  PubMed  CAS  Google Scholar 

  40. Kim KA, Park PW, Lee OJ, Kang DK, Park JY (2007) Effect of polymorphic CYP3A5 genotype on the single-dose simvastatin pharmacokinetics in healthy subjects. J Clin Pharmacol 47:87–93

    Article  PubMed  CAS  Google Scholar 

  41. Bogman K, Peyer AK, Török M, Künsters E, Drewe J (2001) HMG-CoA reductase inhibitors and P-glycoprotein modulation. Br J Pharmacol 132:1183–1192

    Article  PubMed  CAS  Google Scholar 

  42. Kantola T, Kivisto KT, Neuvonen PJ (1998) Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 64:58–65

    Article  PubMed  CAS  Google Scholar 

  43. Jacobsen W, Kuhn B, Soldner A, Kirchner G, Sewing KF, Kollman PA, Benet LZ, Christians U (2000) Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-coa reductase inhibitor atorvastatin. Drug Metab Disp 28:1369–1378

    CAS  Google Scholar 

  44. Mauro VF (1993) Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 24:195–202

    Article  PubMed  CAS  Google Scholar 

  45. Merck Manuals online medical library: Simvastatin (2010) http://www.merckmanuals.com/professional/lexicomp/simvastatin.html. Accessed 8 August 2011

  46. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report (2002) Circulation 106:3143–3421

    Google Scholar 

  47. Merck Sharp & Dohme Corp (2010) Zocor (simvastatin) package insert. Whitehouse Station, NJ, USA. www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf. Accessed 8 November 2011

Download references

Acknowledgements

The authors would like to thank the principal investigators and the clinical research staff who took part in these studies. They also acknowledge the medical writing support by Patrick Hoggard (medical writer, Gardiner-Caldwell Communications, Macclesfield, UK). Funding to support this service was provided by AstraZeneca.

Author information

Authors and Affiliations

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

    Renli Teng, Patrick D. Mitchell & Kathleen A. Butler

Authors
  1. Renli Teng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrick D. Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathleen A. Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Renli Teng.

Additional information

Sources of support

This phase 1 study was funded by AstraZeneca LP. Medical writing assistance was provided by Patrick Hoggard (medical writer, Gardiner-Caldwell Communications, Macclesfield, UK), Macclesfield, UK; financial assistance to support this service was provided by AstraZeneca LP.

Trial details

AZ study numbers: D5130C0025 (ticagrelor/atorvastatin); D5130C00024 (ticagrelor/simvastatin)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Teng, R., Mitchell, P.D. & Butler, K.A. Pharmacokinetic interaction studies of co-administration of ticagrelor and atorvastatin or simvastatin in healthy volunteers. Eur J Clin Pharmacol 69, 477–487 (2013). https://doi.org/10.1007/s00228-012-1369-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-012-1369-4

Keywords

Search

Navigation