Ticagrelor

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Ticagrelor
Ticagrelor.svg
Ticagrelor ball-and-stick animation.gif
Clinical data
Trade names Brilinta, Brilique, Possia
AHFS/Drugs.com Monograph
MedlinePlus a611050
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 by mouth
ATC code B01AC24 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 36%
Protein binding >99.7%
Metabolism Hepatic (CYP3A4)
Biological half-life 7 hrs (ticagrelor), 8.5 hrs (active metabolite AR-C124910XX)
Excretion Biliary
Identifiers
Synonyms AZD-6140
CAS Number 274693-27-5 YesY
PubChem (CID) 9871419
IUPHAR/BPS 1765
ChemSpider 8047109 N
UNII GLH0314RVC YesY
KEGG D09017 YesY
ChEMBL CHEMBL398435 N
ECHA InfoCard 100.114.746
Chemical and physical data
Formula C23H28F2N6O4S
Molar mass 522.567 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Ticagrelor (trade name Brilinta, Brilique, and Possia) is a platelet aggregation inhibitor produced by AstraZeneca.

Ticagrelor is an antagonist of the P2Y12 receptor.[1]

The drug was approved for use in the European Union by the European Commission on December 3, 2010.[2][3] The drug was approved by the US Food and Drug Administration on July 20, 2011.[4]

Medical uses[edit]

Ticagrelor is used for the prevention of thrombotic events (for example stroke or heart attack) in people with acute coronary syndrome or myocardial infarction with ST elevation. The drug is combined with acetylsalicylic acid unless the latter is contraindicated.[5] There is no high quality evidence for the use of ticagrelor in non-ST elevation acute coronary syndrome.[6]

The FDA indication for ticagrelor is reduction of the rate of cardiovascular death, myocardial infarction (MI), and stroke in people with acute coronary syndrome or history of myocardial infarction.[citation needed]

AHA/ACC Guidelines (09/2014) state: "It is reasonable to choose ticagrelor over clopidogrel for P2Y12 inhibition treatment in patients with NSTE-ACS treated with early invasive strategy and/or coronary stenting".

Contraindications[edit]

Contraindications for ticagrelor are: active pathological bleeding and a history of intracranial bleeding, as well as reduced liver function and combination with drugs that strongly influence activity of the liver enzyme CYP3A4, because the drug is metabolized via CYP3A4 and excreted via the liver.[5]

Adverse effects[edit]

The most common side effects are shortness of breath (dyspnea, 14%)[7] and various types of bleeding, such as hematoma, nosebleed, gastrointestinal, subcutaneous or dermal bleeding. Ventricular pauses of 3 seconds occur in 5 percent of people in the first week of treatment. Ticagrelor should be administered with caution or avoided in patients with advanced sinoauricular disease.[8] Allergic skin reactions such as rash and itching have been observed in less than 1% of patients.[5]

Interactions[edit]

Inhibitors of the liver enzyme CYP3A4, such as ketoconazole and possibly grapefruit juice, increase blood plasma levels and consequently can lead to bleeding and other adverse effects. Conversely, drugs that are metabolized by CYP3A4, for example simvastatin, show increased plasma levels and more side effects if combined with ticagrelor. CYP3A4 inductors, for example rifampicin and possibly St. John's wort, can reduce the effectiveness of ticagrelor. There is no evidence for interactions via CYP2C9.

The drug also inhibits P-glycoprotein (P-gp), leading to increased plasma levels of digoxin, ciclosporin and other P-gp substrates. Levels of ticagrelor and AR-C124910XX (the active metabolite of ticagrelor formed by O-deethylation[9]) are not significantly influenced by P-gp inhibitors.[5]

In the US a boxed warning states that use of ticagrelor with aspirin doses exceeding 100 mg/day decreases the effectiveness of the medication.[10]

Chemistry[edit]

Ticagrelor is a nucleoside analogue: the cyclopentane ring is similar to the sugar ribose, and the nitrogen rich aromatic ring system resembles the nucleobase purine, giving the molecule an overall similarity to adenosine. The substance has low solubility and low permeability under the Biopharmaceutics Classification System.[2]

Ticagrelor as a nucleoside analogue
The nucleoside adenosine for comparison

Pharmacokinetics[edit]

Ticagrelor is absorbed quickly from the gut, the bioavailability being 36%, and reaches its peak concentration after about 1.5 hours. The main metabolite, AR-C124910XX, is formed quickly via CYP3A4 by de-hydroxyethylation at position 5 of the cyclopentane ring.[11] It peaks after about 2.5 hours. Both ticagrelor and AR-C124910XX are bound to plasma proteins (>99.7%), and both are pharmacologically active. Blood plasma concentrations are linearly dependent on the dose up to 1260 mg (the sevenfold daily dose). The metabolite reaches 30–40% of ticagrelor's plasma concentrations. Drug and metabolite are mainly excreted via bile and feces.

Plasma concentrations of ticagrelor are slightly increased (12–23%) in elderly patients, women, patients of Asian ethnicity, and patients with mild hepatic impairment. They are decreased in patients that described themselves as 'coloured' and those with severe renal impairment. These differences are considered clinically irrelevant. In Japanese people, concentrations are 40% higher than in Caucasians, or 20% after body weight correction. The drug has not been tested in patients with severe hepatic impairment.[5]

Mechanism of action[edit]

Like the thienopyridines prasugrel, clopidogrel and ticlopidine, ticagrelor blocks adenosine diphosphate (ADP) receptors of subtype P2Y12. In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it an allosteric antagonist, and the blockage is reversible.[12] Moreover, the drug does not need hepatic activation, which might work better for patients with genetic variants regarding the enzyme CYP2C19 (although it is not certain whether clopidogrel is significantly influenced by such variants).[13][14][15]

Comparison with clopidogrel[edit]

The PLATO trial[16] found that ticagrelor had better mortality rates than clopidogrel (9.8% vs. 11.7%, p<0.001) in treating patients with acute coronary syndrome. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke but had greater chances of non-lethal bleeding (16.1% vs. 14.6%, p=0.0084) and higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, p=0.03). While the patient group on ticagrelor had more instances of fatal intracranial bleeding, there were significantly fewer cases of fatal non-intracranial bleeding, leading to an overall neutral effect on fatal or life-threatening bleeding vs. clopidogrel (p=0.70). Rates of major bleeding were not different. Discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (in 7.4% of patients vs. 6.0%, p<0.001).[17]

The PLATO trial showed a statistically insignificant trend toward worse outcomes with ticagrelor versus clopidogrel among US patients in the study – who comprised 1800 of the total 18,624 patients. The HR actually reversed for the composite end point cardiovascular (death, MI, or stroke): 12.6% for patients given ticagrelor and 10.1% for patients given clopidogrel (HR = 1.27). Some believe the results could be due to differences in aspirin maintenance doses, which are higher in the United States.[18] Others state that the central adjudicating committees found an extra 45 MIs in the clopidogrel (comparator) arm but none in the ticagrelor arm, which improved the MI outcomes with ticagrelor. Without this adjudication the trials' primary efficacy outcomes should not be significant.[19]

Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel.[20] This means it has to be taken twice instead of once a day which is a disadvantage in respect of compliance, but its effects are more quickly reversible which can be useful before surgery or if side effects occur.[5][21]

References[edit]

  1. ^ Jacobson, Kenneth A.; Boeynaems, Jean-Marie (July 2010). "P2Y nucleotide receptors: promise of therapeutic applications". Drug Discovery Today. 15 (13-14): 570–578. doi:10.1016/j.drudis.2010.05.011. 
  2. ^ a b "Assessment Report for Brilique" (PDF). European Medicines Agency. January 2011. 
  3. ^ European Public Assessment Report Possia
  4. ^ "FDA approves blood-thinning drug Brilinta to treat acute coronary syndromes". FDA. 20 July 2011. 
  5. ^ a b c d e f Haberfeld, H, ed. (2010). Austria-Codex (in German) (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag. 
  6. ^ Bellemain-Appaix, A.; Kerneis, M.; O'Connor, S. A.; Silvain, J.; Cucherat, M.; Beygui, F.; Barthelemy, O.; Collet, J.-P.; Jacq, L.; Bernasconi, F.; Montalescot, G. (24 October 2014). "Reappraisal of thienopyridine pretreatment in patients with non-ST elevation acute coronary syndrome: a systematic review and meta-analysis". BMJ. 349: g6269–g6269. doi:10.1136/bmj.g6269. PMC 4208629Freely accessible. PMID 25954988. 
  7. ^ Brilinta: Highlights of prescribing information
  8. ^ 6
  9. ^ Teng, R; Oliver, S; Hayes, MA; Butler, K (September 2010). "Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects.". Drug metabolism and disposition: the biological fate of chemicals. 38 (9): 1514–21. doi:10.1124/dmd.110.032250. PMID 20551239. 
  10. ^ Husten L (July 20, 2011). "AstraZeneca: Ticagrelor (Brilinta) Gains FDA Approval ?". CardioBrief. Blog at WordPress.com. 
  11. ^ Teng R, Oliver S, Hayes MA, Butler K (September 2010). "Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects". Drug Metab. Dispos. 38 (9): 1514–21. doi:10.1124/dmd.110.032250. PMID 20551239. 
  12. ^ Birkeland K, Parra D, Rosenstein R (2010). "Antiplatelet therapy in acute coronary syndromes: focus on ticagrelor". J Blood Med. 1: 197–219. doi:10.2147/JBM.S9650. PMC 3262315Freely accessible. PMID 22282698. 
  13. ^ Spreitzer H (February 4, 2008). "Neue Wirkstoffe - AZD6140". Österreichische Apothekerzeitung (in German) (3/2008): 135. 
  14. ^ Owen RT, Serradell N, Bolos J (2007). "AZD6140". Drugs of the Future. 32 (10): 845–853. doi:10.1358/dof.2007.032.10.1133832. 
  15. ^ [unreliable medical source?] Tantry US, Bliden KP, Wei C, Storey RF, Armstrong M, Butler K, Gurbel PA (December 2010). "First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies". Circ Cardiovasc Genet. 3 (6): 556–66. doi:10.1161/CIRCGENETICS.110.958561. PMID 21079055. 
  16. ^ [unreliable medical source?] Cannon CP, Harrington RA, James S, Ardissino D, Becker RC, Emanuelsson H, Husted S, Katus H, Keltai M, Khurmi NS, Kontny F, Lewis BS, Steg PG, Storey RF, Wojdyla D, Wallentin L (January 2010). "Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study". Lancet. 375 (9711): 283–93. doi:10.1016/S0140-6736(09)62191-7. PMID 20079528. 
  17. ^ [unreliable medical source?] 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, Harrington RA, Freij A, Thorsén M (September 2009). "Ticagrelor versus clopidogrel in patients with acute coronary syndromes". N. Engl. J. Med. 361 (11): 1045–57. doi:10.1056/NEJMoa0904327. PMID 19717846. 
  18. ^ Lombo B, Díez JG (2011). "Ticagrelor: the evidence for its clinical potential as an oral antiplatelet treatment for the reduction of major adverse cardiac events in patients with acute coronary syndromes". Core Evid. 6: 31–42. doi:10.2147/CE.S9510. PMC 3065559Freely accessible. PMID 21468241. 
  19. ^ Serebruany VL, Atar D (September 2012). "Viewpoint: Central adjudication of myocardial infarction in outcome-driven clinical trials--common patterns in TRITON, RECORD, and PLATO?". Thromb. Haemost. 108 (3): 412–4. doi:10.1160/TH12-04-0251. PMID 22836596. 
  20. ^ Miller, R (24 February 2010). "Is there too much excitement for ticagrelor?". TheHeart.org. 
  21. ^ H. Spreitzer (17 January 2011). "Neue Wirkstoffe - Elinogrel". Österreichische Apothekerzeitung (in German) (2/2011): 10. 
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