title: Retrospective analysis of electrocardiographic changes after administration of oral or intravenous garenoxacin in five phase I, placebo-controlled studies in healthy volunteers.
abstract: BACKGROUND
  Certain fluoroquinolones and macrolide antibiotics have been associated with prolongation of the corrected QT (QTc) interval or QT dispersion, leading to cardiac arrhythmias. Garenoxacin is a des-F(6)-quinolone with broad-spectrum antimicrobial activity and a favorable pharmacokinetic/pharmacodynamic profile. Its effects on electrocardiographic (ECG) parameters in healthy volunteers have not been reported.
  
  
  OBJECTIVE
  The cardiac safety profile of garenoxacin was further examined using data from healthy volunteers enrolled in 5 dose-ranging and comparative Phase I clinical studies.
  
  
  METHODS
  This was a retrospective analysis of 5 randomized, double-blind, placebo-controlled studies in which 224 healthy volunteers received oral or intravenous garenoxacin (50-1200 mg/d) for 1 to 28 days' dosing duration (<or=14 days' therapeutic duration). The effects of garenoxacin on the QT interval corrected using Bazett's formula (QTcB) and Fridericia's formula (QTcF) and the PR interval were assessed by counts of outliers, linear regressions, and exposure-response plots. Absence of a concentration-dependent effect of garenoxacin on changes from baseline ECG parameters was concluded if the 95% CI for the linear regression slopes of derived QTc- or PR-interval parameters relative to Cmax and C(avg0-12) (average garenoxacin plasma concentration from 0-12 hours after dosing) values for garenoxacin contained zero.
  
  
  RESULTS
  No clinically relevant changes in the QTc or PR intervals were observed over a range of garenoxacin plasma concentrations (Cmax: 0.5-38.6 microg/mL, oral dose range; 3.36-21.4 microg/mL, intravenous dose range). No volunteer had a prolongation from baseline that exceeded established thresholds for the QTcB or QTcF interval (>450 milliseconds for men, >470 milliseconds for women) or the PR interval (>250 milliseconds). One subject had a change in QTcB of 67 milliseconds 4 hours after administration of garenoxacin 400 mg PO on day 7, but the actual value was 418 milliseconds (baseline, 351 milliseconds); the corresponding change in QTcF was 49 milliseconds (actual, 408 milliseconds; baseline, 359 milliseconds). The means for other derived ECG parameters were generally similar between garenoxacin-treated volunteers and placebo controls.
  
  
  CONCLUSIONS
  In this retrospective analysis of data from healthy volunteers, garenoxacin had no clinically relevant dose-, route-of-administration-, or concentration-dependent effects on the QTc or PR interval across a dose range from 50 to 1200 mg/d.
authors: Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. zaiqi.wang@spcorp.com
authors: Zaiqi
authors: Z
authors: Wang
authors: Dennis M
authors: DM
authors: Grasela
authors: Gopal
authors: G
authors: Krishna
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects* / Q000379:methods / Q000706:statistics & numerical data*; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; C419689:garenoxacin