OTO-201: nonclinical assessment of a sustained-release ciprofloxacin hydrogel for the treatment of otitis media

Abstract

Hypothesis: OTO-201 can provide sustained release to the middle ear and effectively treat otitis media, when compared with FDA-approved ciprofloxacin otic drop formulations.

Background: There is an unmet medical need for antibiotic therapy that can provide a full course of treatment from a single administration by an otolaryngologist at the time of tympanostomy tube placement, obviating the need for twice daily multiday treatment with short-acting otic drops.

Methods: Studies in guinea pigs and chinchillas were conducted. OTO-201 was administered as a single intratympanic injection and compared with the twice daily multi-day treatment with Ciprodex or Cetraxal otic drops.

Results: OTO-201 demonstrated sustained release of ciprofloxacin in the middle ear compartment for days to approximately 2 weeks depending on the dose. The substantial C(max) values and steady drug exposure yielded by OTO-201 were in contrast to the pulsatile short lasting exposure seen with Ciprodex and Cetraxal. OTO-201 was also effective in a preclinical chinchilla model of Streptococcus pneumoniae-induced otitis media. The degree of cure was comparable to that afforded by Ciprodex and Cetraxal. There was no evidence of middle or inner ear pathology in guinea pigs treated with OTO-201, unlike Ciprodex and Cetraxal, which both demonstrated mild cochlear ototoxicity. No adverse effects of the poloxamer 407 vehicle were noted.

Conclusion: Intratympanic injection of OTO-201 constitutes an attractive treatment option to twice daily multiday dosing with ciprofloxacin ear drops for the treatment of otitis media, as evidenced by superior middle ear drug exposure, efficacy in an acute otitis media model, safety of administration, and convenience of a single dose regimen.

FIG. 1

Middle ear free ciprofloxacin levels after administration of OTO-201, Ciprodex or Cetraxal. A, Female guinea pigs received a single IT-ANT injection of various doses of OTO-201: 0.06% (closed inverted triangles), 0.2% (stars), 0.6% (closed circles), 2% (closed triangles), 6% (closed squares), and 12% OTO-201 (closed diamonds). A twice-daily for 7 days course of Ciprodex (B) or Cetraxal (C) administered through a tympanostomy tube was given. Free drug levels of ciprofloxacin, obtained by lavaging the middle ear, were determined at the indicated times. (B and C) Predicted profile of ciprofloxacin by combining peak and trough levels. Left inset: peak levels; right inset: trough levels. Data are presented as mean ± SEM (n = 4 ears per group per time point).

FIG. 2

Middle ear epithelium (tissue-bound) ciprofloxacin levels following administration of OTO-201, Ciprodex or Cetraxal. A, Female guinea pigs received a single IT-ANT injection of various doses of OTO-201: 0.6% (closed circles), 2% (closed triangles), 6% (closed squares), or 12% (closed diamonds). A twice-daily for 7 days course of Ciprodex (B) or Cetraxal (C) administered through a tympanostomy tube was given. Tissue-bound levels of ciprofloxacin, obtained by harvesting the middle ear epithelium, were determined at the indicated times. (B and C) Predicted profile of ciprofloxacin by combining peak and trough levels. Left inset: peak levels; right inset: trough levels. Data are presented as mean ± SEM (n = 4 ears per group per time point).

FIG. 3

Inner ear ciprofloxacin levels following administration of OTO-201, Ciprodex or Cetraxal. A, Guinea pigs received a single IT-ANT injection of various doses of OTO-201: 0.6% (closed circles), 2% (closed triangles), 6% (closed squares), or 12% (closed diamonds). A twice-daily for 7 days course of Ciprodex (B) or Cetraxal (C) administered through a tympanostomy tube was given. Perilymph levels of ciprofloxacin were determined at the indicated times. (B and C) Predicted profile of ciprofloxacin by combining peak and trough levels. Left inset: peak levels; right inset: trough levels. Data are presented as mean ± SEM (n = 4 ears per group per time point).

FIG. 4

Middle ear bacterial load and effusion volume in chinchillas with otitis media treated with OTO-201, Ciprodex, or Cetraxal. Otitis media was induced by middle ear inoculation of S. pneumoniae. Immediately before drug administration (at Day 3 postinoculation), the middle ear was drained of effusion and a tympanostomy tube placed. Chinchillas received either a single IT-ANT injection of various doses of OTO-201, or a twice daily for 3 days treatment course of Ciprodex (CPD) or Cetraxal (CTX). The bacterial titer and effusion volume in the middle ear were determined. Data are presented as mean ± SEM (n = 6–13 ears).

FIG. 5

Time to clinical cure in chinchillas with otitis media treated with OTO-201 or Ciprodex. Otitis media was induced by middle ear inoculation of S. pneumoniae. Immediately before drug administration (at Day 3 postinoculation), the middle ear was drained of effusion, and a tympanostomy tube was placed. Chinchillas received either a single IT-ANT injection of various doses of OTO-201, or a twice daily for 3 days treatment course of Ciprodex. The bacterial titer was determined at the indicated times. Data are presented as mean ± SEM (n = 6–10 ears). Arrows refer to the time of administration of OTO-201 or Ciprodex.

FIG. 6

Middle ear ciprofloxacin levels in chinchillas with otitis media treated with OTO-201, Ciprodex or Cetraxal. The levels of free ciprofloxacin in the middle ear of treated chinchillas with OM was determined. Three days posttreatment initiation, middle ear samples were collected, and the concentration of ciprofloxacin was determined. Data are presented as mean ± SEM (n = 6–13 ears). CPD: Ciprodex, CTX: Cetraxal.

FIG. 7

Auditory function following administration of OTO-201 or Cetraxal. The auditory function of male and female guinea pigs was monitored using ABRs at baseline and termination (28 d). Animals received a single IT-ANT injection of poloxamer 407 vehicle, 2% or 6% OTO-201, or a twice daily for 7 days treatment course of Cetraxal. Hearing threshold shifts were reported at low (4 kHz), medium (10 kHz), and high (20 kHz) frequencies. Data are presented as mean ± SEM (n = 5 per sex per group).

FIG. 8

Middle ear histology after administration of OTO-201, Ciprodex, or Cetraxal. Male and female guinea pigs (n = 5 per sex, per group) received a single IT-ANT injection of poloxamer 407 vehicle, 2% or 6% OTO-201, or a twice daily for 7 days treatment course of Ciprodex or Cetraxal. Representative tissue sections of the middle ear (at termination, 28 d) from guinea pigs treated with saline (A), gentamicin (B), P407 vehicle (C), 2% OTO-201 (D), 6% OTO-201 (E), Ciprodex (F), and Cetraxal (G) are presented. Legend: M: malleus, S: stapes, TM: tympanic membrane. Arrows make references of the following: (A) foamy macrophages; (B) upper arrow: fibroplasia and inflammation, lower arrow: mixed cellular and proteinaceous debris; (C) foamy macrophages; (D) foamy macrophages; (E) granulomatous inflammation; (F) reactive cells; (G) basophilic foamy macrophages.

FIG. 9

Inner ear cytocochleogram after administration of OTO-201, Ciprodex, or Cetraxal. Male and female guinea pigs (n = 5 per sex, per group) received a single IT-ANT injection of poloxamer 407 vehicle, 2% or 6% OTO-201, or a twice daily for 7 days treatment course of Ciprodex or Cetraxal. Representative cytocochleograms (at termination, 28 d) mapping the presence or absence of inner hair cells (black line) and the 3 rows of outer hairs (Row 1, light gray line; Row 2, gray line; Row 3, dark gray line) by position along the cochlear spiral, with apex on the left and base on the right, from the cochleae of treated guinea pigs having received saline (A), gentamicin (B), P407 vehicle (C), 2% OTO-201 (D), 6% OTO-201 (E), Ciprodex (F), and Cetraxal (G).

FIG. 10

Tympanostomy tube patency. Pictures of the tympanic membrane region depicting the patency at Days 1 and 3 after IT-ANT administration in guinea pigs of poloxamer 407 vehicle (dyed with Evans Blue), immediately before tympanostomy tube placement.