title: Dependence of hearing changes on the dose of intratympanically applied gentamicin: a meta-analysis using mathematical simulations of clinical drug delivery protocols.
abstract: OBJECTIVE
  To establish safe dosing protocols for the treatment of patients with Meniere's disease with intratympanic gentamicin.
  
  
  METHODS
  A validated computer model of gentamicin dispersion in the inner ear fluids was used to calculate cochlear drug levels resulting from specific clinical delivery protocols. Dosing in the cochlea was compared with changes of hearing sensitivity for 568 patients reported in 19 publications.
  
  
  METHODS
  Cochlear drug levels were calculated based on the concentration and volume of gentamicin applied, the time the drug remained in the middle ear, and on the specific timing of injections. Time courses were quantified in terms of the maximum concentration (Cmax) and the area under the curve of the drug at specific cochlear locations.
  
  
  RESULTS
  Drug levels resulting from single, "one-shot" injections were typically lower than those from repeated or continuous application protocols. Comparison of hearing sensitivity changes with gentamicin dosing revealed a flat curve with a near-zero mean for lower doses, suggesting that hearing changes with doses over this range were probably unrelated to the applied drug. Higher intracochlear doses were generated with repeated or continuous delivery protocols, which in some cases caused substantial hearing losses and an increased incidence of deafened ears.
  
  
  CONCLUSIONS
  One-shot application protocols produce gentamicin doses in the cochlea that have minimal risk to hearing at the frequencies tested. Repeated or continuous application protocols result in higher doses that in some cases damage hearing. The high variability of hearing changes, even with low gentamicin doses, calls into question the rationale for using individual hearing changes to titrate the applied dose.
authors.affiliation: Department of Otolaryngology, Washington University School of Medicine, St Louis, Missouri 63110, USA. salta@msnotes.wustl.edu
authors.forename: Alec N
authors.initials: AN
authors.lastname: Salt
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Gill
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Plontke
mesh_terms: D003051:Cochlea / Q000378:metabolism; D003198:Computer Simulation; D007758:Ear, Inner / Q000378:metabolism; D004432:Ear, Middle; D005839:Gentamicins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006309:Hearing / Q000187:drug effects*; D006801:Humans; D007267:Injections; D008575:Meniere Disease / Q000188:drug therapy; D008954:Models, Biological
chemical_list: D005839:Gentamicins