Toxicological Sciences, Vol 52, 101-106, Copyright © 1999 by Society of Toxicology
J Mordenti, K Thomsen, V Licko, L Berleau, JW Kahn, RA Cuthbertson, ET Duenas, AM Ryan, C Schofield, TW Berger, YG Meng and J Cleland
Poly(lactic-co-glycolic) acid (PLGA) bioresorbable microspheres are used
for controlled-release drug delivery and are particularly promising for
ocular indications. The objective of the current study was to evaluate the
pharmacokinetics and safety of a recombinant human monoclonal antibody
(rhuMAb HER2) in rabbits after bolus intravitreal administration of a
solution or a PLGA-microsphere formulation. On Day 0, forty-eight male New
Zealand white rabbits (2.3-2.6 kg) were immobilized with intramuscular
ketamine/xylazine, and the test materials were injected directly into the
vitreous compartment. Group 1 animals received rhuMAb HER2 in 50:50
lactide: glycolide PLGA microspheres; Group 2 animals received rhuMAb HER2
in solution (n = 24/group). The dose for each eye was 25 microg (50
microl). After dosing, animals were sacrificed at 2 min, and on 1, 2, 4, 7,
14, 23, 29, 37, 44, 50, and 56 days (n = 2/timepoint/group). Safety
assessment included direct ophthalmoscopy, clinical observations, body
weight, and hematology and clinical chemistry panels. At necropsy, vitreous
and plasma were collected for pharmacokinetics and analysis for antibodies
to rhuMAb HER2, and the vitreal pellet (Group 1) was prepared for
histologic evaluation. All animals completed the study per protocol- both
treatments were well tolerated, and no suppurative or mixed inflammatory
cell reaction was observed in the vitreal samples (Group 1) at any of the
time points examined. Antibodies to rhuMAb HER2 were detected in plasma
samples by Day 7 in both treatment groups, but infrequently in vitreous
samples. There were no safety implications associated with this immune
response. The in vitro characterization of the PLGA microspheres provided
reasonable projections of the in vivo rhuMAb HER2 release kinetics (Group
1). The total amount of antibody that was released was similar in vitro
(25.9%) and in vivo (32.4%). RhuMAb HER2 (Group 2) was cleared slowly from
the vitreous compartment, with initial and terminal half-lives of 0.9 and
5.6 days, respectively. The volume of distribution approximated the
vitreous volume in a rabbit eye.
ARTICLES
Intraocular pharmacokinetics and safety of a humanized monoclonal antibody in rabbits after intravitreal administration of a solution or a PLGA microsphere formulation
Department of Experimental Therapeutics, Genentech, Inc., South San Francisco, California 94080, USA. Joyce@axyspharm.com
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