Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD.

BACKGROUND: Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking. METHODS: Fifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5 mg), bevacizumab (1.25 mg), or aflibercept (2.0 mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections. RESULTS: Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10 pg/mL) as early as 3 h postdose until ≥7 days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4 pg/mL compared with baseline of 17 pg/mL. CONCLUSIONS: There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF. TRIAL REGISTRATION NUMBER: NCT02118831.

Intravitreal ranibizumab for macular edema secondary to central retinal vein occlusion.

PURPOSE: To evaluate the safety and efficacy of intravitreal ranibizumab for macular edema secondary to central retinal vein occlusion. METHODS: Patients with macular edema secondary to perfused central retinal vein occlusion were enrolled in this ongoing, prospective, open-label study. Treatment was initiated with monthly intravitreal ranibizumab for 3 months. In the first year, additional injections were administered for edema in quarterly intervals as needed (PRN) for Cohort 1 (n = 10) and monthly PRN for Cohort 2 (n = 10). In the second year of treatments, all patients received monthly PRN treatment. Early Treatment Diabetic Retinopathy Study best-corrected visual acuity, central retinal thickness, fundus photographs, and fluorescein angiograms were evaluated, and the incidence and severity of adverse events were documented. RESULTS: Mean change in best-corrected visual acuity and central retinal thickness improved during the induction phase in both groups. During the remainder of the first year for Cohort 1, initial gains were lost during quarterly treatment but returned with monthly PRN treatment in the second year. For Cohort 2, improvement in best-corrected visual acuity and central retinal thickness from the induction phase was maintained through Month 24. Nineteen of 20 patients experienced a reduction in intraretinal hemorrhage, optic nerve swelling, and/or venous diameter after treatment. One myocardial infarction, one cerebrovascular accident, and no serious ocular adverse events were reported. Iris neovascularization was developed in none of the eyes. CONCLUSION: Ranibizumab was well tolerated and associated with a greater reduction in macular edema and improvement in visual acuity in the monthly PRN regimen compared with quarterly treatment. Vision lost during the quarterly PRN injection intervals in the first year of Cohort 1 could be regained by switching to monthly PRN dosing.

Intravitreal bevacizumab (Avastin) in the treatment of macular edema secondary to branch retinal vein occlusion.

PURPOSE: To report the authors' experience after intravitreal bevacizumab (Avastin, Genentech) injection in patients with macular edema (ME) secondary to branch retinal vein occlusive disease (BRVO). METHODS: A consecutive retrospective review of patients with ME secondary to BRVO who were treated with intravitreal bevacizumab (1.25 mg/0.05 mL). Patients underwent complete ophthalmic evaluation, which included nonstandardized Snellen visual acuity testing, optical coherence tomography (OCT), and/or angiographic testing at baseline and follow-up visits. RESULTS: There were 27 consecutive patients who received intravitreal bevacizumab injections. The mean length of follow-up was 5.3 months (median 6 months, range 3-8 months). The mean visual acuity improved from 20/200(-) at baseline to 20/100(-) at 1 month and 20/100(+) at 3 months and last follow-up (P < 0.001). The mean central 1 mm macular thickness was 478 microm at baseline and decreased to 310, 336, and 332 microm at 1 month, 3 months, and last follow-up (P < 0.001). Patients received an average of two injections (range one to three). No adverse side effects were observed following injections. CONCLUSION: The observed anatomic (by ophthalmic examination, OCT, and/or fluorescence angiography) and visual acuity improvements and lack of serious adverse side effects after intravitreal bevacizumab injection demonstrates, in principle, the potential of bevacizumab for the treatment of ME in this setting.

Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy.

PURPOSE: To report the biologic effect of intravitreal bevacizumab in patients with retinal and iris neovascularization secondary to diabetes mellitus. DESIGN: Interventional, consecutive, retrospective, case series. PARTICIPANTS: Forty-five eyes of 32 patients with retinal and/or iris neovascularization secondary to diabetes mellitus. METHODS: Patients received intravitreal bevacizumab (6.2 microg-1.25 mg). Ophthalmic evaluations included nonstandardized Snellen visual acuity (VA), complete ophthalmic examination, fluorescein angiography, and optical coherence tomography. MAIN OUTCOME MEASURES: Change in fluorescein angiographic leakage of the proliferative diabetic retinopathy (PDR). Secondary outcomes included changes in Snellen VA. RESULTS: No significant ocular or systemic adverse events were observed. All patients with neovascularization demonstrated by fluorescein angiography (44/44 eyes) had complete (or at least partial) reduction in leakage of the neovascularization within 1 week after the injection. Complete resolution of angiographic leakage of neovascularization of the disc was noted in 19 of 26 (73%) eyes, and leakage of iris neovascularization completely resolved in 9 of 11 (82%) eyes. The leakage was noted to diminish as early as 24 hours after injection. In addition to the reduction in angiographic leakage, the neovascularization clinically appeared to involute in many patients with a reduction in the caliber or presence of perfused blood vessels. In 2 cases, a subtle decrease in leakage of retinal or iris neovascularization in the fellow uninjected eye was noted, raising the possibility that therapeutic systemic levels were achieved after intravitreal injection. Recurrence of fluorescein leakage varied. Recurrent leakage was seen as early as 2 weeks in one case, whereas in other cases, no recurrent leakage was noted at last follow-up of 11 weeks. CONCLUSIONS: Short-term results suggest that intravitreal bevacizumab is well tolerated and associated with a rapid regression of retinal and iris neovascularization secondary to PDR. A consistent biologic effect was noted, even with the lowest dose (6.2 microg) tested, supporting proof of concept. The observation of a possible therapeutic effect in the fellow eye raises concern that systemic side effects are possible in patients undergoing treatment with intravitreal bevacizumab (1.25 mg), and lower doses may achieve a therapeutic result with less risk of systemic side effects. Further study is indicated.

Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.

PURPOSE: To report the short-term safety, biologic effect, and a possible mechanism of action of intravitreal bevacizumab in patients with neovascular age-related macular degeneration (AMD). DESIGN: Interventional, consecutive, retrospective case series. PARTICIPANTS: Eighty-one eyes of 79 patients with subfoveal neovascular AMD. METHODS: Patients received intravitreal bevacizumab (1.25 mg) on a monthly basis until macular edema, subretinal fluid (SRF), and/or pigment epithelial detachment (PED) resolved. Ophthalmic evaluations included nonstandardized Snellen visual acuity (VA), complete ophthalmic examination, fluorescein angiography, and optical coherence tomography (OCT). MAIN OUTCOME MEASURES: Assessments of safety, changes in Snellen VA, OCT retinal thickness, and angiographic lesion characteristics were performed. RESULTS: No significant ocular or systemic side effects were observed. Most patients (55%) had a reduction of >10% of baseline retinal thickness at 1 week after the injection. At 4 weeks after injection, 30 of 81 eyes demonstrated complete resolution of retinal edema, SRF, and PEDs. Of the 51 eyes with 8 weeks' follow-up, 25 had complete resolution of retinal thickening, SRF, and PEDs. At 1, 4, 8,and 12 weeks, the mean retinal thickness of the central 1 mm was decreased by 61, 92, 89, and 67 mum, respectively (P<0.0001 for 1, 4, and 8 weeks and P<0.01 for 12 weeks). At 4 and 8 weeks, mean VA improved from 20/200 to 20/125 (P<0.0001). Median vision improved from 20/200 to 20/80(-) at 4 weeks and from 20/200 to 20/80 at 8 weeks. CONCLUSIONS: Short-term results suggest that intravitreal bevacizumab (1.25 mg) is well tolerated and associated with improvement in VA, decreased retinal thickness by OCT, and reduction in angiographic leakage in most patients, the majority of whom had previous treatment with photodynamic therapy and/or pegaptanib. Further evaluation of intravitreal bevacizumab for the treatment of choroidal neovascularization is warranted.

A prospective, open-label, dose-escalating study of low molecular weight heparin during repeat vitrectomy for PVR and severe diabetic retinopathy.

BACKGROUND: To determine the maximum tolerated dose (MTD) of enoxaparin, a low molecular weight heparin (LMWH) was used during repeat vitrectomy for rhegmatogenous retinal detachment with proliferative vitreoretinopathy (PVR) and severe diabetic retinopathy. METHODS: From 25 patients, 29 eyes undergoing repeat vitrectomy for PVR (CP3 or greater) or severe diabetic retinopathy were included in the study. Patients had previously undergone an average of 2.1 previous vitrectomies (range 1-5). Enoxaparin was added to the infusion fluid in an escalating dose from 0.1 IU/ml to 6.0 IU/ml as tolerated. Intraoperative bleeding, postoperative fibrin, hyphema and vitreous hemorrhage were graded in an unmasked fashion using previously described grading scales. RESULTS: All patients completed the study, and the study was able to achieve the 6.0 IU/ml maximum dose on the dose escalation schedule. No patient experienced dose-limiting toxicity. Analysis showed no increase in intraoperative bleeding complications between low dose (1.0 IU/ml) enoxaparin (Mann-Whitney Test, P=0.029). CONCLUSIONS: Enoxaparin dose escalation did not result in a dose-dependent increase in acute side effects. The establishment of a well-tolerated dose of enoxaparin during repeat vitrectomy for PVR and severe diabetic retinopathy (6.0 IU/ml) provides a foundation for future studies.