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Nonclinical safety and pharmacokinetics of intravitreally administered human-derived plasmin in rabbits and minipigs.

Authors
  • Proksch, Joel W1
  • Driot, Jean-Yves
  • Vandeberg, Pete
  • Ward, Keith W
  • 1 Global Preclinical Development, Bausch & Lomb, Rochester, NY 14609, USA. [email protected]
Type
Published Article
Journal
Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics
Publication Date
Jun 01, 2008
Volume
24
Issue
3
Pages
320–332
Identifiers
DOI: 10.1089/jop.2007.0120
PMID: 18476803
Source
Medline
Language
English
License
Unknown

Abstract

The use of plasmin for pharmacologic vitreolysis and the creation of a posterior vitreous detachment offers several potential advantages over surgery. The nonclinical pharmacokinetics and safety of human-derived plasmin was evaluated following single or multiple intravitreal injections to rabbits and minipigs. Single intravitreal injections of plasmin at 45-900 microg resulted in a no adverse effect level (NOAEL) of 45 microg in both species; effects at higher doses included chemosis, mucopurulent discharge, mononuclear cell infiltrates in the iris-ciliary body, and reversible changes in electroretinogram waveforms and parameters. No retinal histopathology abnormalities were observed. Following 4 weekly intravitreal injections at 4-423 microg, a NOAEL of 4 microg was identified. Effects at the higher doses included myosis, iritis, iridolenticular synechiae, and changes in electroretinogram waveforms and parameters that were generally not reversible in the present investigation. Vitreal plasmin concentrations were highest at 30 min after dosing and decreased rapidly; measurable concentrations remained, in some animals, at 24 h. Intravitreal plasmin exposure increased in a less-than-dose-proportional manner and tended to be lower in minipigs than in rabbits. The current findings demonstrate acceptable nonclinical safety and pharmacokinetics of intravitreal human plasmin in rabbits and minipigs and support the clinical development of plasmin for ocular diseases.

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