title: Pharmacodynamic evaluation of pantoprazole therapy on clopidogrel effects: results of a prospective, randomized, crossover study.
abstract: BACKGROUND
  Safety concerns have recently emerged based on a drug interaction between clopidogrel and proton pump inhibitors leading to reduced pharmacodynamic effects. However, whether such drug interaction is a class effect or a drug effect and if this can be modulated by timing of drug administration remains a matter of debate. The aim of this study was to assess the impact of high-dose pantoprazole therapy, a proton pump inhibitor with low potential to interfere with clopidogrel metabolism, administered concomitantly or staggered, on clopidogrel-mediated pharmacodynamic effects.
  
  
  RESULTS
  This was a prospective, randomized, crossover study conducted in 20 healthy volunteers. Subjects were randomly assigned to receive pantoprazole (80 mg daily) administered concomitantly (CONC) or staggered by 8 to 12 hours (STAG) for 1 week on a background of clopidogrel therapy (600-mg loading dose followed by a 75-mg maintenance dose during all phases) in a crossover fashion with a 2- to 4-week washout period between treatments. All subjects had a 1-week treatment phase with a clopidogrel-only regimen with a 2- to 4-week washout period from randomization sequence. Platelet function was assessed by flow cytometric analysis of the status of phosphorylation of the vasodilator-stimulated phosphoprotein, light transmittance aggregometry after adenosine diphosphate stimuli, and VerifyNow P2Y(12) system at 3 time points: baseline, 24 hours after loading dose, and 1 week after maintenance dose. The primary end point was the comparison of P2Y(12) reactivity index assessed by vasodilator-stimulated phosphoprotein at 1 week. After 1 week, there were no significant difference in P2Y(12) reactivity index between the CONC and STAG regimens (least-squares mean±SEM, 56.0±3.9% versus 56.1±3.9%; P=0.974), as well as when compared with the clopidogrel-only regimen (61.0±3.9%; P=0.100 versus CONC and P=0.107 versus STAG). Further, no differences were observed at baseline and 24 hours between regimens. Concordant results were obtained by light transmittance aggregometry and VerifyNow P2Y(12) assays.
  
  
  CONCLUSIONS
  Pantoprazole therapy used at high doses is not associated with modulation of the pharmacodynamic effects of clopidogrel, irrespective of timing of drug administration.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01170533.
authors.affiliation: University of Florida College of Medicine-Jacksonville, Jacksonville, FL 32209, USA.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Ferreiro
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ueno
authors.forename: Salvatore D
authors.initials: SD
authors.lastname: Tomasello
authors.forename: Davide
authors.initials: D
authors.lastname: Capodanno
authors.forename: Bhaloo
authors.initials: B
authors.lastname: Desai
authors.forename: Kodlipet
authors.initials: K
authors.lastname: Dharmashankar
authors.forename: Naveen
authors.initials: N
authors.lastname: Seecheran
authors.forename: Murali K
authors.initials: MK
authors.lastname: Kodali
authors.forename: Andrew
authors.initials: A
authors.lastname: Darlington
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Pham
authors.forename: Antonio
authors.initials: A
authors.lastname: Tello-Montoliu
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Charlton
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Bass
authors.forename: Dominick J
authors.initials: DJ
authors.lastname: Angiolillo
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology*; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D001792:Blood Platelets / Q000187:drug effects; D015815:Cell Adhesion Molecules; D000077144:Clopidogrel; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004347:Drug Interactions; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D000077402:Pantoprazole; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011446:Prospective Studies; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D058925:Receptors, Purinergic P2Y12 / Q000187:drug effects; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; C548576:P2RY12 protein, human; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D058925:Receptors, Purinergic P2Y12; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077144:Clopidogrel; D000077402:Pantoprazole; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine