title: Impact of Escalating Loading Dose Regimens of Ticagrelor in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: Results of a Prospective Randomized Pharmacokinetic and Pharmacodynamic Investigation.
abstract: OBJECTIVE
  The goal of this study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of escalating ticagrelor loading dose (LD) regimens in primary percutaneous coronary intervention (PPCI).
  
  
  BACKGROUND
  Patients with ST-segment elevation myocardial infarction undergoing PPCI frequently have suboptimal platelet inhibition in the early hours after ticagrelor LD. The use of high ticagrelor LD regimens has been hypothesized to optimize platelet inhibition in PPCI.
  
  
  METHODS
  This was a prospective, randomized study of escalating ticagrelor LD regimens (180 mg, 270 mg, or 360 mg) in PPCI (N = 52). PK/PD analyses were performed before and 30 min, 1, 2, 4, 8, and 24 h post-LD. PK assessments included exposure to ticagrelor and its metabolite (AR-C124910XX). PD assessments included P2Y12 reaction units (PRU) measured by VerifyNow P2Y12 and platelet reactivity index (PRI) measured by vasodilator-stimulated phosphoprotein (VASP).
  
  
  RESULTS
  Platelet reactivity was elevated during the first 2 h post-LD. There were no differences in PRU between groups during the study time course (p = 0.179). There were no significant differences in PRU levels across groups at all time points, except at 1 h (p = 0.017) where platelet reactivity was lowest with a 270-mg LD. No differences were found between the 180-mg and 360-mg groups (primary endpoint; p > 0.999). High on-treatment platelet reactivity rates were not different across groups, except at 1 hour (p = 0.038). Parallel PD findings were observed with VASP-PRI. PK analysis showed a delay in ticagrelor absorption and generation of AR-C124910XX, irrespective of dose. Although morphine was associated with a delay in ticagrelor PK/PD, it was not an independent predictor of high on-treatment platelet reactivity.
  
  
  CONCLUSIONS
  ST-segment elevation myocardial infarction patients undergoing PPCI frequently exhibit impaired response to ticagrelor in the early hours after drug administration, which cannot be overcome by increasing LD regimens. These PD findings are largely attributed to an impaired PK profile, indicating a delay in drug absorption compared with that reported in stable clinical settings. (High Ticagrelor Loading Dose in STEMI; NCT01898442).
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Francesco
authors.initials: F
authors.lastname: Franchi
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Rollini
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Jung Rae
authors.initials: JR
authors.lastname: Cho
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Mona
authors.initials: M
authors.lastname: Bhatti
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Christopher
authors.initials: C
authors.lastname: DeGroat
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ferrante
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Dunn
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Amit
authors.initials: A
authors.lastname: Nanavati
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Edward
authors.initials: E
authors.lastname: Carraway
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Siva
authors.initials: S
authors.lastname: Suryadevara
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Zenni
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Guzman
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida.
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Bass
authors.affiliation: Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida. Electronic address: dominick.angiolillo@jax.ufl.edu.
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000368:Aged; D001711:Biotransformation; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008840:Microfilament Proteins / Q000097:blood; D008875:Middle Aged; D009203:Myocardial Infarction / Q000175:diagnosis / Q000628:therapy*; D062645:Percutaneous Coronary Intervention / Q000009:adverse effects; D010750:Phosphoproteins / Q000097:blood; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D010979:Platelet Function Tests; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D058925:Receptors, Purinergic P2Y12 / Q000097:blood / Q000187:drug effects; D000077486:Ticagrelor; D016896:Treatment Outcome; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: C561701:AR C124910XX; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; C548576:P2RY12 protein, human; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077486:Ticagrelor; D000241:Adenosine
keywords: ST-segment elevation myocardial infarction; pharmacodynamic; pharmacokinetic; platelets; ticagrelor