Thromb Haemost 2021; 121(06): 755-766
DOI: 10.1055/s-0040-1721773
Cellular Haemostasis and Platelets

Insights from In Vitro and Clinical Data to Guide Transition from the Novel P2Y12 Antagonist Selatogrel to Clopidogrel, Prasugrel, and Ticagrelor

1   Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
,
1   Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
,
Michael Dobrow
2   Biotrial Inc., Newark, New Jersey, United States
,
Martine Baumann
3   Department of Drug Discovery Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
,
3   Department of Drug Discovery Biology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
,
1   Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
,
1   Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
› Author Affiliations
Funding This study was sponsored by Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland.

Abstract

Reduced pharmacodynamic (PD) effects of irreversible oral P2Y12 receptor antagonists have been reported when administered during cangrelor infusion. Therefore, the PD interaction liability of the novel P2Y12 receptor antagonist selatogrel with irreversible (i.e., clopidogrel, prasugrel) and reversible (i.e., ticagrelor) oral P2Y12 receptor antagonists was investigated in vitro and in healthy subjects. In vitro, selatogrel reduced the effects of clopidogrel and prasugrel in a concentration-dependent manner, while additive effects were observed for the combination of selatogrel and ticagrelor. Accordingly, a single-center, randomized, double-blind, two-way crossover study was conducted consisting of six groups. In each group (N = 12), an open-label loading dose of 300 or 600 mg clopidogrel, 60 mg prasugrel, or 180 mg ticagrelor was administered 30 minutes (i.e., at t max of selatogrel) or 12 hours after a single subcutaneous dose of 16 mg selatogrel or placebo. Inhibition of platelet aggregation (IPA) was assessed at various time points up to 48 hours. Reduced IPA was determined when clopidogrel or prasugrel was administered 30 minutes after selatogrel (∼40 and 70% lower IPA, respectively, at 24 hours postdosing). However, when administering prasugrel 12 hours after selatogrel, IPA was not impacted (>90% IPA) and in the case of clopidogrel reduced effects were partially mitigated. Similar IPA was determined for ticagrelor when administered 30 minutes after selatogrel or placebo. In conclusion, reduced IPA was observed for clopidogrel and prasugrel when administered after selatogrel, which can be mitigated by applying an appropriate time interval. No PD interaction with ticagrelor was observed.

Supplementary Material



Publication History

Received: 07 August 2020

Accepted: 04 November 2020

Article published online:
07 January 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Naghavi M, Abajobir AA, Abbafati C. et al; GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017; 390 (10100): 1151-1210
  • 2 Capodanno D, Alfonso F, Levine GN, Valgimigli M, Angiolillo DJ. ACC/AHA versus ESC guidelines on dual antiplatelet therapy: JACC guideline comparison. J Am Coll Cardiol 2018; 72 (23, Pt A): 2915-2931
  • 3 Neumann FJ, Sousa-Uva M, Ahlsson A. et al; ESC Scientific Document Group. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J 2019; 40 (02) 87-165
  • 4 Wallentin L, Becker RC, Budaj A. et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11) 1045-1057
  • 5 Wiviott SD, Braunwald E, McCabe CH. et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357 (20) 2001-2015
  • 6 Akers WS, Oh JJ, Oestreich JH, Ferraris S, Wethington M, Steinhubl SR. Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor: a direct, parenteral P2Y12 receptor antagonist. J Clin Pharmacol 2010; 50 (01) 27-35
  • 7 Angiolillo DJ, Rollini F, Storey RF. et al. International expert consensus on switching platelet P2Y12 receptor-inhibiting therapies. Circulation 2017; 136 (20) 1955-1975
  • 8 Rollini F, Franchi F, Angiolillo DJ. Switching P2Y12-receptor inhibitors in patients with coronary artery disease. Nat Rev Cardiol 2016; 13 (01) 11-27
  • 9 Rollini F, Franchi F, Angiolillo DJ. Switching P2Y12 receptor inhibiting therapies. Interv Cardiol Clin 2017; 6 (01) 67-89
  • 10 Schneider DJ, Seecheran N, Raza SS, Keating FK, Gogo P. Pharmacodynamic effects during the transition between cangrelor and prasugrel. Coron Artery Dis 2015; 26 (01) 42-48
  • 11 Steinhubl SR, Oh JJ, Oestreich JH, Ferraris S, Charnigo R, Akers WS. Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb Res 2008; 121 (04) 527-534
  • 12 Capranzano P, Francaviglia B, Angiolillo DJ. Pharmacodynamics during transition between platelet P2Y12 inhibiting therapies. Interv Cardiol Clin 2019; 8 (04) 321-340
  • 13 Schneider DJ. Transition strategies from cangrelor to oral platelet P2Y12 receptor antagonists. Coron Artery Dis 2016; 27 (01) 65-69
  • 14 Schneider DJ, Agarwal Z, Seecheran N, Keating FK, Gogo P. Pharmacodynamic effects during the transition between cangrelor and ticagrelor. JACC Cardiovasc Interv 2014; 7 (04) 435-442
  • 15 Rollini F, Franchi F, Cho JR. et al. A head-to-head pharmacodynamic comparison of prasugrel vs. ticagrelor after switching from clopidogrel in patients with coronary artery disease: results of a prospective randomized study. Eur Heart J 2016; 37 (35) 2722-2730
  • 16 Juif PE, Boehler M, Dobrow M, Ufer M, Dingemanse J. Clinical pharmacology of the reversible and potent P2Y12 receptor antagonist ACT-246475 after single subcutaneous administration in healthy male subjects. J Clin Pharmacol 2019; 59 (01) 123-130
  • 17 Milluzzo RP, Franchina GA, Capodanno D, Angiolillo DJ. Selatogrel, a novel P2Y12 inhibitor: a review of the pharmacology and clinical development. Expert Opin Investig Drugs 2020; 29 (06) 537-546
  • 18 Sinnaeve P, Fahrni G, Schelfaut D. et al. Subcutaneous selatogrel inhibits platelet aggregation in patients with acute myocardial infarction. J Am Coll Cardiol 2020; 75 (20) 2588-2597
  • 19 Storey RF, Gurbel PA, ten Berg J. et al. Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes. Eur Heart J 2020; 41 (33) 3132-3140
  • 20 Silvain J, Zeitouni M, Kerneis M. Selatogrel for acute myocardial infarction: the promise and challenges of self-medication. J Am Coll Cardiol 2020; 75 (20) 2598-2601
  • 21 Baldoni D, Bruderer S, Krause A. et al. A new reversible and potent P2Y12 receptor antagonist (ACT-246475): tolerability, pharmacokinetics, and pharmacodynamics in a first-in-man trial. Clin Drug Investig 2014; 34 (11) 807-818
  • 22 Paniccia R, Priora R, Liotta AA, Abbate R. Platelet function tests: a comparative review. Vasc Health Risk Manag 2015; 11: 133-148
  • 23 Brandt JT, Payne CD, Wiviott SD. et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007; 153 (01) 66.e9-66.e16
  • 24 Mercuri M, Natarajan MK, Velianou JL. ST-elevation myocardial infarction: is there time for Q waves?. CMAJ 2012; 184 (10) 1125-1126
  • 25 Price MJ, Walder JS, Baker BA. et al. Recovery of platelet function after discontinuation of prasugrel or clopidogrel maintenance dosing in aspirin-treated patients with stable coronary disease: the recovery trial. J Am Coll Cardiol 2012; 59 (25) 2338-2343
  • 26 Li YG, Ni L, Brandt JT. et al. Inhibition of platelet aggregation with prasugrel and clopidogrel: an integrated analysis in 846 subjects. Platelets 2009; 20 (05) 316-327
  • 27 Valgimigli M, Bueno H, Byrne RA. et al; ESC Scientific Document Group, ESC Committee for Practice Guidelines (CPG), ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018; 39 (03) 213-260
  • 28 Farid NA, Kurihara A, Wrighton SA. Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol 2010; 50 (02) 126-142
  • 29 Judge HM, Buckland RJ, Jakubowski JA, Storey RF. Cangrelor inhibits the binding of the active metabolites of clopidogrel and prasugrel to P2Y12 receptors in vitro. Platelets 2016; 27 (03) 191-195
  • 30 Sugidachi A, Ogawa T, Kurihara A. et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel's active metabolite. J Thromb Haemost 2007; 5 (07) 1545-1551
  • 31 Rollini F, Franchi F, Tello-Montoliu A. et al. Pharmacodynamic effects of cangrelor on platelet P2Y12 receptor-mediated signaling in prasugrel-treated patients. JACC Cardiovasc Interv 2014; 7 (04) 426-434
  • 32 Rollini F, Franchi F, Thano E. et al. In vitro pharmacodynamic effects of cangrelor on platelet P2Y12 receptor-mediated signaling in ticagrelor-treated patients. JACC Cardiovasc Interv 2017; 10 (13) 1374-1375
  • 33 Dovlatova NL, Jakubowski JA, Sugidachi A, Heptinstall S. The reversible P2Y antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function. J Thromb Haemost 2008; 6 (07) 1153-1159
  • 34 Angiolillo DJ, Curzen N, Gurbel P. et al. Pharmacodynamic evaluation of switching from ticagrelor to prasugrel in patients with stable coronary artery disease: results of the SWAP-2 study (Switching Anti Platelet-2). J Am Coll Cardiol 2014; 63 (15) 1500-1509
  • 35 Franchi F, Rollini F, Rivas Rios J. et al. Pharmacodynamic effects of switching from ticagrelor to clopidogrel in patients with coronary artery disease: results of the SWAP-4 study. Circulation 2018; 137 (23) 2450-2462
  • 36 Jakubowski JA, Li YG, Small DS. et al. A comparison of the VerifyNow P2Y12 point-of-care device and light transmission aggregometry to monitor platelet function with prasugrel and clopidogrel: an integrated analysis. J Cardiovasc Pharmacol 2010; 56 (01) 29-37
  • 37 Varenhorst C, James S, Erlinge D. et al. Assessment of P2Y(12) inhibition with the point-of-care device VerifyNow P2Y12 in patients treated with prasugrel or clopidogrel coadministered with aspirin. Am Heart J 2009; 157 (03) 562.e1-562.e9
  • 38 Schilling U, Dingemanse J, Ufer M. Pharmacokinetics and pharmacodynamics of approved and investigational P2Y12 receptor antagonists. Clin Pharmacokinet 2020; 59 (05) 545-566
  • 39 Cui YM, Wang ZN, Chen XW, Zhang HL, Zhao X, Zhou Y. Pharmacokinetics and pharmacodynamics of single and multiple doses of prasugrel in healthy native Chinese subjects. Acta Pharmacol Sin 2012; 33 (11) 1395-1400