Abstract
Purpose: :
To study anodal iontophoretic delivery of the commercial formulation and a new iontophoretic formulation of Avastin® in vivo using the Visulex iontophoresis system.
Methods: :
All studies were performed under anodal iontophoresis (AI) on New Zealand white rabbits using a Visulex device system with 2.5% bevacizumab (Avastin®). For pharmacokinetics (PK) studies (n=6) the commercial Avastin® formulation and an enhanced (A0-01) iontophoretic formulation were used in Group 1 and 2, respectively. After 20 min of AI delivery, the rabbits were sacrificed and the eyes enucleated. The eyes were dissected and the cornea, aqueous humor, vitreous, conjunctiva, sclera, choroid and retina were assayed for drug concentrations with ELISA. For the safety study Group 3 (n=6), the eyes were examined with an indirect ophthalmoscope before and immediately after iontophoretic dosing, then again on days 2, 4, and 6. The eyes were graded according to a modified McDonald-Shaddock scale for conjunctival injection, chemosis, corneal haze, iritis and other ocular irritation signs. At day 6, the animals were sacrificed and all eyes were processed for histopathological examination.
Results: :
The total amount of Avastin® delivered into the eye after 20 min of AI (1.8 mA/cm2) was 223 ± 71 µg and 315 ± 123 µg for the commercial formulation and (A0-01) iontophoretic formulation, respectively. High concentrations of Avastin were distributed in the conjunctiva and sclera tissues. However, approximately 4 µg was delivered to the retina/choroid tissues. For the safety study, the only adverse effect noted was very minor conjunctival injection, present in four of the six eyes treated on Day 2 which resolved by Day 6. Histopathological evaluation showed no effects due to the iontophoretic treatment.
Conclusions: :
This study demonstrated promising results toward higher Avastin® delivery with the new iontophoretic formulation (AO-01), although this is not statistically significant. Further modifications are required to the new formulation to achieve significant enhanced delivery. The amount delivered to the retina/choroid using the Visulex iontophoretic system is within same order of magnitude reported in literature using intravitreal injection. This study is among the first to demonstrate safe delivery of Avastin® in vivo to the posterior eye tissues within the therapeutic range using iontophoresis.
Keywords: age-related macular degeneration • drug toxicity/drug effects • ocular irritancy/toxicity testing