Anatomic and pharmacokinetic properties of intravitreal bevacizumab and ranibizumab after vitrectomy and lensectomy.

PURPOSE: To determine the anatomic characteristics and pharmacokinetic properties of intravitreally placed bevacizumab and ranibizumab after pars plana lensectomy or pars plana vitrectomy and to compare these with nonoperated control eyes in a rabbit model. METHODS: Three groups of six Dutch-belted rabbits each underwent pars plana vitrectomy, pars plana lensectomy, or served as nonsurgical controls. Twelve days after surgery, 3 rabbits from each group underwent intravitreal injection in one eye with 1.25 mg/0.05 mL I-124-bevacizumab or 0.5 mg/0.05 mL I-124-ranibizumab. Serial imaging with integrated positron emission and computed tomography (PET/CT) were obtained on Days 0, 2, 5, 7, 14, 21, 28, and 35. Measured radioactivity emission in becquerels/milliliter was used to calculate the half-lives for each agent. RESULTS: The intravitreally placed radiolabeled agents were contained within the vitreous cavity for the duration of the study. The average clearance half-lives with standard error for bevacizumab and ranibizumab after correction for radioactive decay were, respectively, 4.22 ± 0.07 days and 2.81 ± 0.05 days in unoperated eyes, 2.30 ± 0.09 days (P < 0.0001) and 2.13 ± 0.05 days (P < 0.0001) after vitrectomy, and 2.08 ± 0.07 days (P = 0.0001) and 1.79 ± 0.05 days (P < 0.0001) after lensectomy. CONCLUSION: Intravitreal retention was longer for bevacizumab than ranibizumab within all study groups and was significantly reduced after vitrectomy and lensectomy for both agents. Consideration for more frequent intravitreal anti-vascular endothelial growth factor dosing regimens may be made for patients whose treated eyes have undergone previous vitrectomy or who are aphakic.

The effect of intravitreal bevacizumab and ranibizumab on cutaneous tensile strength during wound healing.

PURPOSE: To investigate the effect of intravitreal bevacizumab and ranibizumab on wound tension and by histopathology during cutaneous wound healing in a rabbit model and to compare this effect to placebo intravitreal saline controls 1 and 2 weeks following intravitreal injection. METHODS: A total of 120 New Zealand white rabbits were randomly assigned to one of three treatment groups each consisting of 40 rabbits. Each group received intravitreal injections of bevacizumab, ranibizumab, or normal saline. Immediately afterwards, each rabbit underwent four 6 mm full-thickness dermatologic punch biopsies. Twenty rabbits from each agent group underwent wound harvesting on day 7 or day 14. The skin samples were stained for CD34 for vascular endothelial cells on day 7, and maximal wound tensile load was measured on days 7 and 14. Quantitative assessment of mean neovascularization (MNV) scores was obtained from 10 contiguous biopsy margin 400× fields of CD34-stained sections by two independent observers. RESULTS: Wound tension reading means (N) with standard error and adjusted P-values on day 7 were: saline placebos, 7.46 ± 0.87; bevacizumab, 4.50 ± 0.88 (P = 0.041); and ranibizumab, 4.67 ± 0.84 (P = 0.025). On day 14 these were: saline placebos, 7.34 ± 0.55; bevacizumab, 6.05 ± 0.54 (P = 0.18); and ranibizumab 7.99 ± 0.54 (P = 0.40). MNV scores in CD34 stained sections were: saline controls, 18.31 ± 0.43; bevacizumab, 11.02 ± 0.45 (P < 0.0001); and ranibizumab, 13.55 ± 0.43 (P < 0.0001). The interobserver correlation coefficient was 0.928. CONCLUSION: At day 7, both anti-vascular endothelial growth factor (anti-VEGF) agents had significantly suppressed MNV scores and exerted a significant reduction of cutaneous wound tensile strength compared with saline controls. At day 14, neither agent produced a significant effect on tensile wound strength. Since angiogenesis is an integral component of the proliferative phase of wound healing, we encourage clinicians to be aware of their patients' recent surgical history during intravitreal anti-VEGF therapy and to consider refraining from their use during the perioperative period.

Serum levels of intravitreal bevacizumab after vitrectomy, lensectomy and non-surgical controls.

PURPOSE: To determine serum level differences of intravitreally-placed bevacizumab after vitrectomy and lensectomy-vitrectomy and to compare these with non-operated eyes in a rabbit model. METHODS: Five Dutch-belted rabbits underwent pars plana vitrectomy (PPV), five rabbits underwent pars plana lensectomy (PPL) and five rabbits served as non-surgical controls. Twelve days following the surgical procedures, each operated eye underwent an intravitreal injection consisting of 1.25 mg/0.05 mL bevacizumab. Serum levels from each rabbit were drawn on days 2, 4, 7, 10, 14, 21, 28 and 35 and were measured with ELISA immunoassay. RESULTS: The average peak serum concentration (Cmax) was highest for the PPL group (11.33 µg ± 3.48 mL), and was similar between the PPV (5.35 µg ± 2.69 mL) and non-surgical control groups (5.35 µg ± 0.69 mL). The average time to maximal plasma concentration (Tmax) in days was earliest for the PPL group (2.8 ± 0.47), followed by the PPV (5.6 ± 0.84) and non-surgical control groups (6.4 ± 0.71). The PPL group had higher serum levels than the other two groups until day 7 that was significant only at day 2 (p < 0.0001). After day 4, there were no significant differences or trends between any of the three groups. The half-life (T1/2) was fastest for the PPL group (1.41 ± 0.21 d) followed by the PPV (2.80 ± 3.35 d) and non-surgical control groups (6.69 ± 10.4 d). CONCLUSIONS: Serum bevacizumab levels were initially elevated following lensectomy and vitrectomy compared to non-surgical eyes following intravitreal injection. The half-life of bevacizumab was prolonged in non-surgical eyes presumably due to a slower release from the vitreous cavity.

The effect of intravitreal anti-VEGF agents on peripheral wound healing in a rabbit model.

PURPOSE: To investigate the effect of intravitreal pegaptanib, bevacizumab, and ranibizumab on blood-vessel formation during cutaneous wound healing in a rabbit model and to compare this effect to placebo controls. METHODS: Forty New Zealand albino rabbits underwent full thickness cutaneous wounds using 6-mm dermatologic punch biopsies. The rabbits were assigned to four groups of ten, each receiving intravitreal injections of pegaptanib, bevacizumab, ranibizumab, or no injection (untreated controls). Five rabbits from each group underwent wound harvesting on day 7 and five from each group on day 14. The skin samples were stained with hematoxylin and eosin (HE), Masson's trichrome (MT), and CD34 for vascular endothelial cells. Semiquantitative evaluation of HE- and MT-stained slides was performed by one pathologist. Quantitative assessment of mean neovascularization (MNV) scores was obtained from five contiguous biopsy margin 400× fields of CD34-stained sections by four independent observers. RESULTS: Week 1 MNV scores in CD-34 stained sections were: untreated controls: 11.51 ± 4.36; bevacizumab: 7.41 ± 2.82 (P = 0.013); ranibizumab: 8.71 ± 4.08 (P = 0.071); and pegaptanib: 10.15 ± 5.59 (P = 0.378). Week 2 MNV data were: untreated controls: 6.14 ± 2.25; bevacizumab: 7.25 ± 2.75 (P = 0.471); ranibizumab: 4.53 ± 3.12 (P = 0.297); and, pegaptanib: 6.35 ± 3.09 (P = 0.892). Interobserver variability using intraclass correlation coefficient was 0.961. CONCLUSIONS: At week 1, all three anti-VEGF agents had suppressed MNV scores compared to controls. Although not statistically significant, there was an inhibitory trend, particularly with bevacizumab and ranibizumab. These effects were diminished at 2 weeks, reflecting a transition between the proliferative and remodeling phases of wound healing.