Pharmacokinetics of Bevacizumab After Topical, Subconjunctival and Intravitreal Administration In Rabbits
Hiroyuki Nomoto 1*,
Fumio Shiraga 2,
Noriyuki Kuno 3,
Erika Kimura 3,
Shinobu Fujii 4,
Katsuhiko Shinomiya 4,
ALEXANDER K NUGENT 5,
Kazuyuki Hirooka 6,
and
Tetsuya Baba 2
1 Ophthalmology, Kagawa University Faculty of Medicine, Miki-cho, Kagawa, Japan; Ophthalmology, Stanford University School of Medicine, Stanford, California, United States
2 Ophthalmology, Kagawa University Faculty of Medicine, Miki-cho, Japan
3 Research and Development Center, Santen Pharmaceutical Co., Ltd, Ikoma, Nara, Japan
4 Research and Development Center, Santen Pharmaceutical Co., Ltd, Ikoma-shi, Nara, Japan
5 Ophthalmology, Stanford University School of Medicine, Stanford, California, United States
6 Ophthalmology, Kagawa University Faculty of Medicine, Miki-cho, Kagawa, Japan
* To whom correspondence should be addressed. E-mail: nomoto{at}med.kagawa-u.ac.jp.
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Abstract |
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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 (1.25mg/0.05mL; 6 times daily dose for the first seven days) single subconjunctival injection (1.25mg/0.05mL) or single intravitreal injection (1.25mg/0.05mL). 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: For intravitreal injection in the administrated eye, the mean maximum concentration of bevacizumab (Cmax) in the iris/ciliary body and retina/choroid were 109192.6 ng/g and 93990.0 ng/g, respectively, while for subconjunctival injection, the Cmax was 1418.7 ng/g, and 295.8 ng/g, respectively. In the fellow eyes, when 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 were 1192.9 ng/g and 187.0 ng/g, respectively. For eye-drops, bevacizumab only a small level was detected in the iris/ciliary body and retina/choroid. Systemic exposure of bevacizumab when administered by intravitreal and subconjunctival injection was the same level.
Conclusions: Intravitreal injection of bevacizumab was the most effective route of administration for intraocular tissue. Also, bevacizumab injected subconjunctivally was transported into intraocular tissues of treated eyes with effective level. Both intravitreal and subconjunctival injection of bevacizumab resulted in high concentrations in the plasma and bevacizumab was distributed into the intraocular tissues in fellow eyes via systemic circulation. This might be effective for blocking vascular endothelial growth factor activities.
Key Words:
pharmacokinetics, drug delivery, drug penetration
