title: Role of mixed ion channel effects in the cardiovascular safety assessment of the novel anti-MRSA fluoroquinolone JNJ-Q2.
abstract: OBJECTIVE
  JNJ-Q2, a novel broad-spectrum fluoroquinolone with anti-methicillin-resistant Staphylococcus aureus activity, was evaluated in a comprehensive set of non-clinical and clinical cardiovascular safety studies. The effect of JNJ-Q2 on different cardiovascular parameters was compared with that of moxifloxacin, sparfloxacin and ofloxacin. Through comparisons with these well-known fluoroquinolones, the importance of effects on compensatory ion channels to the cardiovascular safety of JNJ-Q2 was investigated.
  
  
  METHODS
  JNJ-Q2 and comparator fluoroquinolones were evaluated in the following models/test systems: hERG-transfected HEK293 cells sodium channel-transfected CHO cells, guinea pig right atria, arterially perfused rabbit left ventricular wedge preparations and in vivo studies in anaesthetized guinea pigs, anaesthetized and conscious telemetered dogs, and a thorough QT study in humans.
  
  
  RESULTS
  The trend for effects of JNJ-Q2 on Tp-Te, QT, QRS and PR intervals in the non-clinical models and the plateau in QTc with increasing plasma concentration in humans are consistent with offsetting sodium and calcium channel activities that were observed in the non-clinical studies. These mixed ion channel activities result in the less pronounced or comparable increase in QTc interval for JNJ-Q2 compared with moxifloxacin and sparfloxacin despite its greater in vitro inhibition of I(Kr).
  
  
  CONCLUSIONS
  Based on the non-clinical and clinical cardiovascular safety assessment, JNJ-Q2 has a safe cardiovascular profile for administration in humans with comparable or reduced potential to prolong QT intervals, compared with moxifloxacin. The results demonstrate the importance of compensatory sodium and calcium channel activity in offsetting potassium channel activity for compounds with a fluoroquinolone core.
authors.affiliation: Janssen Research & Development, LLC., a division of Janssen Pharmaceutical Companies of Johnson & Johnson, Drug Safety Sciences, Raritan, NJ 08869, USA. geichenb@its.jnj.com
authors.forename: G
authors.initials: G
authors.lastname: Eichenbaum
authors.forename: M K
authors.initials: MK
authors.lastname: Pugsley
authors.forename: D J
authors.initials: DJ
authors.lastname: Gallacher
authors.forename: R
authors.initials: R
authors.lastname: Towart
authors.forename: G
authors.initials: G
authors.lastname: McIntyre
authors.forename: U
authors.initials: U
authors.lastname: Shukla
authors.forename: J M
authors.initials: JM
authors.lastname: Davenport
authors.forename: H R
authors.initials: HR
authors.lastname: Lu
authors.forename: J
authors.initials: J
authors.lastname: Rohrbacher
authors.forename: V
authors.initials: V
authors.lastname: Hillsamer
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000494:pharmacology*; D016275:Atrial Function / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D015220:Calcium Channels / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D018592:Cross-Over Studies; D004285:Dogs; D004311:Double-Blind Method; D005260:Female; D024841:Fluoroquinolones / Q000097:blood / Q000494:pharmacology*; D006168:Guinea Pigs; D057809:HEK293 Cells; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D015221:Potassium Channels / Q000502:physiology*; D011817:Rabbits; D015222:Sodium Channels / Q000502:physiology*; D016276:Ventricular Function / Q000187:drug effects
chemical_list: C550935:7-(3-(2-amino-1-fluoroethylidene)-1-piperidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid; D000900:Anti-Bacterial Agents; D015220:Calcium Channels; D024841:Fluoroquinolones; D015221:Potassium Channels; D015222:Sodium Channels