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Role of mixed ion channel effects in the cardiovascular safety assessment of the novel anti‐MRSA fluoroquinolone JNJ‐Q2
Author(s) -
Eichenbaum G,
Pugsley MK,
Gallacher DJ,
Towart R,
McIntyre G,
Shukla U,
Davenport JM,
Lu HR,
Rohrbacher J,
Hillsamer V
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.01874.x
Subject(s) - sparfloxacin , moxifloxacin , medicine , qt interval , herg , pharmacology , safety pharmacology , cardiology , ofloxacin , potassium channel , antibiotics , chemistry , drug , biochemistry , ciprofloxacin
BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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 AND IMPLICATIONS 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.