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.
Similar content being viewed by others
References
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
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
Husted S, van Giezen JJJ (2009) Ticagrelor: The first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther 27:259–274
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
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
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
BrilintaTM, US full prescribing information (July 2011) http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022433s000lbl.pdf. Accessed 8 November 2011
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Lennernäs H (2003) Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 42:1141–1160
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
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
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
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
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
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
Bottorff MB (2006) Statin safety and drug interactions: clinical implications. Am J Cardiol 97(Suppl):27C–31C
Bellosta S, Paoletti R, Corsini A (2004) Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation 109(Suppl III):50–57, III
Jacobson TA (2004) Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 94:1140–1146
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
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
Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M (2006) SLCO1B1 Polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics 16:873–879
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
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
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
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
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
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
Kantola T, Kivisto KT, Neuvonen PJ (1998) Effect of itraconazole on the pharmacokinetics of atorvastatin. Clin Pharmacol Ther 64:58–65
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
Mauro VF (1993) Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 24:195–202
Merck Manuals online medical library: Simvastatin (2010) http://www.merckmanuals.com/professional/lexicomp/simvastatin.html. Accessed 8 August 2011
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
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
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
Corresponding author
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
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-012-1369-4