title: OTO-104: a sustained-release dexamethasone hydrogel for the treatment of otic disorders.
abstract: OBJECTIVE
  To investigate whether OTO-104, a poloxamer-based hydrogel containing micronized dexamethasone for intratympanic delivery, can provide long-lasting inner ear exposure and be well tolerated.
  
  
  METHODS
  OTO-104 was administered intratympanically to guinea pigs and sheep, and its pharmacokinetic and toxicity profiles were examined.
  
  
  RESULTS
  After a single intratympanic injection of OTO-104 (from 0.6% to 20%, w/w), significant and prolonged exposure to dexamethasone in the inner ear was observed. Increasing the concentration of OTO-104 resulted in higher perilymph drug levels as well as a more prolonged duration of exposure. At the highest dose, therapeutic perilymph levels of dexamethasone could be sustained over 3 months in guinea pigs and more than 1 month in sheep. A toxicologic evaluation was conducted, including assessments of middle and inner ear function and physiology, as well as appraisal of local and systemic toxicity. A small and transient shift in hearing threshold was observed, most probably conductive in nature. No significant histologic changes in middle or inner ear tissues were noted. Although macroscopically mild erythema/inflammation was documented in a subset of guinea pigs treated with 20% OTO-104, the nature and the severity of these changes were not different between the poloxamer vehicle, saline, and 20% OTO-104 groups. No evidence of acute dermal toxicity, delayed hypersensitivity, or systemic adverse effects was found.
  
  
  CONCLUSIONS
  OTO-104 is a novel proprietary therapeutic delivery system that can achieve prolonged, sustained release of dexamethasone within the inner ear fluids. The administration of this clinical candidate formulation via intratympanic injection is expected to be well tolerated both locally and systemically.
authors.affiliation: Otonomy Inc., San Diego, California 92121, USA. fpiu@otonomy.com
authors.forename: Fabrice
authors.initials: F
authors.lastname: Piu
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.forename: Rayne
authors.initials: R
authors.lastname: Fernandez
authors.forename: Luis
authors.initials: L
authors.lastname: Dellamary
authors.forename: Anne
authors.initials: A
authors.lastname: Harrop
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ye
authors.forename: Jenifer
authors.initials: J
authors.lastname: Sweet
authors.forename: Rachel
authors.initials: R
authors.lastname: Tapp
authors.forename: David F
authors.initials: DF
authors.lastname: Dolan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Altschuler
authors.forename: Jay
authors.initials: J
authors.lastname: Lichter
authors.forename: Carl
authors.initials: C
authors.lastname: LeBel
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations; D003907:Dexamethasone / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D007758:Ear, Inner / Q000737:chemistry*; D006168:Guinea Pigs; D020100:Hydrogels / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D007267:Injections; D010498:Perilymph / Q000737:chemistry*; D012756:Sheep
chemical_list: D003692:Delayed-Action Preparations; D020100:Hydrogels; D003907:Dexamethasone