title: Intraocular pharmacokinetics and safety of a humanized monoclonal antibody in rabbits after intravitreal administration of a solution or a PLGA microsphere formulation.
abstract: 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.
authors.affiliation: Department of Experimental Therapeutics, Genentech, Inc., South San Francisco, California 94080, USA. Joyce@axyspharm.com
authors.forename: J
authors.initials: J
authors.lastname: Mordenti
authors.forename: K
authors.initials: K
authors.lastname: Thomsen
authors.forename: V
authors.initials: V
authors.lastname: Licko
authors.forename: L
authors.initials: L
authors.lastname: Berleau
authors.forename: J W
authors.initials: JW
authors.lastname: Kahn
authors.forename: R A
authors.initials: RA
authors.lastname: Cuthbertson
authors.forename: E T
authors.initials: ET
authors.lastname: Duenas
authors.forename: A M
authors.initials: AM
authors.lastname: Ryan
authors.forename: C
authors.initials: C
authors.lastname: Schofield
authors.forename: T W
authors.initials: TW
authors.lastname: Berger
authors.forename: Y G
authors.initials: YG
authors.lastname: Meng
authors.forename: J
authors.initials: J
authors.lastname: Cleland
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics*; D001672:Biocompatible Materials; D016503:Drug Delivery Systems; D006801:Humans; D019344:Lactic Acid; D008297:Male; D008863:Microspheres; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D011817:Rabbits; D012995:Solubility; D012996:Solutions; D014822:Vitreous Body
chemical_list: D000911:Antibodies, Monoclonal; D001672:Biocompatible Materials; D011108:Polymers; D012996:Solutions; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid