title: Intravenous Clopidogrel (MDCO-157) Compared with Oral Clopidogrel: The Randomized Cross-Over AMPHORE Study.
abstract: BACKGROUND
  The extent of P2Y12 inhibition during coronary intervention is an important determinant of ischemic complications. The currently available oral P2Y12 inhibitors are limited by a relatively slow onset of action and variable on-treatment response.
  
  
  OBJECTIVE
  Our objective was to determine the pharmacodynamic (PD) dose-antiplatelet response relationship and the pharmacokinetics of MDCO-157, an intravenous formulation of clopidogrel complexed with sulphobutylether betacyclodextrin, and to identify the dose level of MDCO-157 that matches the PD effect of oral clopidogrel 300 mg.
  
  
  METHODS
  A randomized open-label crossover study was performed in 33 healthy adult volunteers to determine the pharmacokinetic (clopidogrel and clopidogrel H4 thiol active metabolite) and the PD (vasodilator-stimulated phosphoprotein [VASP]) effects of MDCO-157 at doses of 75, 150, and 300 mg and of oral clopidogrel 300 mg.
  
  
  RESULTS
  Data are presented as %, mean (standard deviation). The maximum effect of P2Y12 receptor inhibition assessed by flow cytometry using VASP was 70.42 (6.7), 69.45 (7.1), and 65.58 (12.6) for intravenous MDCO-157 at doses of 75, 150, and 300 mg, respectively, compared with 56.6 (17.5) with oral clopidogrel 300 mg administration (p < 0.0001). Intravenous administration of MDCO-157 led to a stepwise increase in plasma exposure of clopidogrel, higher than with administration of an oral dose of 300 mg (p < 0.0001). Plasma exposure of H4-thiol also increased with intravenous dose (3.6 ± 2.6, 6.9 ± 4.6, and 12.4 ± 9.1 h·ng/ml for intravenous 75, 150, and 300 mg, respectively) but was lower than with oral administration of a 300-mg dose (34.0 ± 16.0 h.ng/ml; pairwise p < 0.0001).
  
  
  CONCLUSIONS
  MDCO-157, an intravenous formulation of clopidogrel complexed with sulphobutylether betacyclodextrin, did not show significant platelet inhibition when administered at doses up to 300 mg. Higher doses with longer infusion may be needed to reach a sufficient threshold of active metabolite generation.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT01860105.
authors.affiliation: Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (AP-HP), Sorbonne Universités UPMC (Paris 6), Paris, France.|ACTION Study Group, Institut de Cardiologie, Bureau 2-236, Pitié-Salpêtrière University Hospital, 47 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Collet
authors.affiliation: Department of Pharmacology and CIC-1421, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.|INSERM, CIC-1421 and UMR ICAN 1166, Paris, France.|Faculty of Medicine, Department of Pharmacology and UMR ICAN 1166, Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Funck-Brentano
authors.affiliation: The Medicine Company, Parsippany, NJ, USA.
authors.forename: Jayne
authors.initials: J
authors.lastname: Prats
authors.affiliation: Department of Pharmacology and CIC-1421, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.|INSERM, CIC-1421 and UMR ICAN 1166, Paris, France.|Faculty of Medicine, Department of Pharmacology and UMR ICAN 1166, Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
authors.forename: Joe-Elie
authors.initials: JE
authors.lastname: Salem
authors.affiliation: Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (AP-HP), Sorbonne Universités UPMC (Paris 6), Paris, France.|ACTION Study Group, Institut de Cardiologie, Bureau 2-236, Pitié-Salpêtrière University Hospital, 47 Boulevard de l'Hôpital, 75013, Paris, France.|Department of Pharmacology and CIC-1421, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.|INSERM, CIC-1421 and UMR ICAN 1166, Paris, France.|Faculty of Medicine, Department of Pharmacology and UMR ICAN 1166, Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.affiliation: Department of Pharmacology and CIC-1421, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.|INSERM, CIC-1421 and UMR ICAN 1166, Paris, France.
authors.forename: Edith
authors.initials: E
authors.lastname: Guilloux
authors.affiliation: The Medicine Company, Parsippany, NJ, USA.
authors.forename: Ming-yi
authors.initials: MY
authors.lastname: Hu
authors.affiliation: Biotranex LLC, Monmouth Junction, NJ, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: He
authors.affiliation: Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (AP-HP), Sorbonne Universités UPMC (Paris 6), Paris, France.|ACTION Study Group, Institut de Cardiologie, Bureau 2-236, Pitié-Salpêtrière University Hospital, 47 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Johanne
authors.initials: J
authors.lastname: Silvain
authors.affiliation: Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (AP-HP), Sorbonne Universités UPMC (Paris 6), Paris, France.|ACTION Study Group, Institut de Cardiologie, Bureau 2-236, Pitié-Salpêtrière University Hospital, 47 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gallois
authors.affiliation: Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (AP-HP), Sorbonne Universités UPMC (Paris 6), Paris, France.|ACTION Study Group, Institut de Cardiologie, Bureau 2-236, Pitié-Salpêtrière University Hospital, 47 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Brugier
authors.affiliation: Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (AP-HP), Sorbonne Universités UPMC (Paris 6), Paris, France.|ACTION Study Group, Institut de Cardiologie, Bureau 2-236, Pitié-Salpêtrière University Hospital, 47 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Ghalia
authors.initials: G
authors.lastname: Anzaha
authors.affiliation: Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (AP-HP), Sorbonne Universités UPMC (Paris 6), Paris, France.|ACTION Study Group, Institut de Cardiologie, Bureau 2-236, Pitié-Salpêtrière University Hospital, 47 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Galier
authors.affiliation: Department of Pharmacology and CIC-1421, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.|INSERM, CIC-1421 and UMR ICAN 1166, Paris, France.|Faculty of Medicine, Department of Pharmacology and UMR ICAN 1166, Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Nicolas
authors.affiliation: Institut de Cardiologie, INSERM_UMRS 1166, Pitié-Salpêtrière Hospital (AP-HP), Sorbonne Universités UPMC (Paris 6), Paris, France. gilles.montalescot@psl.aphp.fr.|ACTION Study Group, Institut de Cardiologie, Bureau 2-236, Pitié-Salpêtrière University Hospital, 47 Boulevard de l'Hôpital, 75013, Paris, France. gilles.montalescot@psl.aphp.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Montalescot
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000077144:Clopidogrel; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin; D000077144:Clopidogrel; D013988:Ticlopidine