title: Safety assessment of subconjunctivally implanted devices containing latanoprost in Dutch-belted rabbits.
abstract: OBJECTIVE
  Latanoprost is used for the treatment of an increased intraocular pressure (IOP) to prevent the progression of glaucoma. Since the lack of compliance with topical ocular dosing may compromise efficacy, alternate methods of delivery are being sought. A 9-month study was conducted to assess the safety and tolerability of latanoprost-containing subconjunctivally implanted devices.
  
  
  METHODS
  Dutch-belted rabbits were implanted subconjunctivally with up to 5 placebo or drug-loaded devices containing from 50 to 180 μg of latanoprost per device. Study assessment consisted of irritation scoring, clinical signs, ophthalmic exams, IOP, electroretinography (ERG), ocular histology of cohorts at 3 and 9 months postimplantation, and systemic exposure to latanoprost acid.
  
  
  RESULTS
  The implants were well tolerated, with minimal-to-mild clinical and microscopic ocular findings attributable to either the placebo or drug-loaded devices. Mild conjunctival congestion persisted through week 13 of the study and tended to correlate with the number of devices and presence of drug. Ophthalmic examinations revealed no effects beyond conjunctival surface hyperemia. No effects on the IOP, corneal thickness, or ERG parameters were observed. The lack of changes in the IOP was expected due to the known lack of the IOP-lowering effects in rabbits from latanoprost. Microscopically, implants at the 3-month necropsy were associated with subconjunctival tissue cavities (containing the implants), fibrous encapsulation, and an infiltrate of lymphocytes and macrophages, sometimes as multinucleate cells, into the subconjunctival implant cavity. The drug-containing implants were often associated with inflammatory cell infiltrates, including heterophils (neutrophils), within the implant subconjunctival cavities and adjacent to the implant sites. At the 9-month necropsy, heterophils were no longer common among the inflammatory cell infiltrates; macrophages and lymphocytes persisted; most of the biodegradable implants were fragmented and disintegrating; and fibrovascular proliferation was present within implant luminal remnants. None of the findings were considered adverse. Systemic exposures were above the limit of quantification (0.1 ng/mL) for up to 96 h in the higher-dose groups, consistent with the initial burst phase of compound release.
  
  
  CONCLUSIONS
  Overall, the study supports the safety of the latanoprost-containing subconjunctival device as a means of extended delivery of the antiglaucoma medication. Latanoprost-containing subconjunctival implants were well tolerated by Dutch-belted rabbits for up to 9 months. Such devices may improve patient compliance and serve as a means of extended delivery of antiglaucoma medications.
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research and Development, San Diego, CA 92121, USA. bart.jessen@pfizer.com
authors.forename: Bart A
authors.initials: BA
authors.lastname: Jessen
authors.forename: Michael H I
authors.initials: MH
authors.lastname: Shiue
authors.forename: Harjeet
authors.initials: H
authors.lastname: Kaur
authors.forename: Paul
authors.initials: P
authors.lastname: Miller
authors.forename: Robert
authors.initials: R
authors.lastname: Leedle
authors.forename: Hong
authors.initials: H
authors.lastname: Guo
authors.forename: Mark
authors.initials: M
authors.lastname: Evans
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D003228:Conjunctiva / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D004343:Drug Implants; D004596:Electroretinography; D005260:Female; D007429:Intraocular Pressure / Q000187:drug effects; D000077338:Latanoprost; D008297:Male; D009887:Ophthalmoscopy; D011461:Prostaglandins F, Synthetic / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits
chemical_list: D000959:Antihypertensive Agents; D004343:Drug Implants; D011461:Prostaglandins F, Synthetic; D000077338:Latanoprost