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Originally published In Press as doi:10.1167/iovs.08-3148 on March 25, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:4807-4813.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-3148
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Pharmacokinetics of Bevacizumab after Topical, Subconjunctival, and Intravitreal Administration in Rabbits

Hiroyuki Nomoto,1,2 Fumio Shiraga,1 Noriyuki Kuno,3 Erika Kimura,3 Shinobu Fujii,3 Katsuhiko Shinomiya,3 Alex K. Nugent,2 Kazuyuki Hirooka,1 and Tetsuya Baba1

1From the Department of Ophthalmology, Kagawa University Faculty of Medicine, Kagawa, Japan; the 2Department of Ophthalmology, Stanford University School of Medicine, Stanford, California; and the 3Research and Development Center, Santen Pharmaceutical Co., Ltd., Nara, Japan.

PURPOSE. To investigate the pharmacokinetics of bevacizumab in rabbits for three different routes of administrations: intravitreal injection, subconjunctival injection, and eye drops.

METHODS. Pigmented rabbits received bevacizumab in one eye by topical eye drops (1.25 mg/0.05 mL six times daily for the first 7 days), single subconjunctival injection (1.25 mg/0.05 mL), or single intravitreal injection (1.25 mg/0.05 mL). Bevacizumab concentrations in plasma and ocular tissues in the treated and fellow eyes were determined by sandwich enzyme-linked immunosorbent assay at 1, 2, 4, and 12 weeks after administration.

RESULTS. After intravitreal injection in the treated eye, the mean maximum concentrations (Cmax) of bevacizumab in the iris/ciliary body and retina/choroid were 109,192.6, and 93,990.0 ng/g, respectively, whereas after subconjunctival injection, the Cmax was 1418.7 and 295.8 ng/g, respectively. In the fellow eyes, when the drug was administered by intravitreal injection, the Cmax was 753.6 ng/g in the iris/ciliary body and 224.2 ng/g in the retina/choroid and by subconjunctival injection was 1192.9 and 187.0 ng/g, respectively. With eye drops, only a small level of bevacizumab was detected in the iris/ciliary body and retina/choroid. Systemic exposure to bevacizumab was at the same level when administered by intravitreal or subconjunctival injection.

CONCLUSIONS. Intravitreal injection of bevacizumab was the most effective route of administration for intraocular tissue. Also, bevacizumab injected subconjunctivally was transported into the intraocular tissues of the treated eyes at an effective level. Both intravitreal and subconjunctival injections of bevacizumab resulted in high plasma concentrations. Bevacizumab was distributed into the intraocular tissues in fellow eyes via the systemic circulation. This treatment may be effective for blocking vascular endothelial growth factor activity.






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