Nathan Steinle

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.

Systemic Pharmacokinetics And Pharmacodynamics Of Intravitreal Aflibercept, Bevacizumab, And Ranibizumab

Purpose: To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO). Methods: Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab (0.5 mg for AMD/RVO, 0.3 mg for DME). The main outcome measures were serum PKs and plasma free-VEGF concentrations after the first and third injections. Results: A total of 151 patients were included. In AMD/DME/RVO, systemic exposure to each drug was highest with bevacizumab, then aflibercept, and lowest with ranibizumab. Ranibizumab cleared from the bloodstream more quickly than bevacizumab or aflibercept. Aflibercept treatment resulted in the greatest reductions in plasma free-VEGF relative to baseline levels, whereas ranibizumab treatment resulted in the smallest decreases in plasma free-VEGF. Conclusion: The three anti-VEGF treatments examined in this analysis demonstrated notable differences in systemic PKs. Generally, the reduction in plasma free-VEGF levels correlated with elevated levels of circulating anti-VEGF agents, with the reduction in free-VEGF levels greatest with aflibercept and least with ranibizumab.

Outer retina reflectivity changes on sd-oct after intravitreal ocriplasmin for vitreomacular traction and macular hole.

Purpose: To report initial experience with intravitreal ocriplasmin (IVO) and to describe outer retina reflectivity changes observed on spectral domain optical coherence tomography (SD-OCT) after IVO injection in patients with vitreomacular traction (VMT) with or without macular holes (MHs). Methods: A consecutive retrospective review of patients with VMT and MH who were treated with IVO was performed. Patients underwent complete ophthalmic evaluation, including nonstandardized Snellen visual acuity testing, and SD-OCT at baseline and follow-up visits. Results: A total of 23 patients who received IVO for VMT and/or MH were included for analysis. Patient age ranged from 53 years to 93 years with a mean of 74 years. The mean follow-up was 174 days (range: 20–291 days). Vitreomacular traction release at Day 30 after IVO was achieved in 11 of 23 patients (47.82%), at an average of 14.54 days (range: 1–30 days) after treatment. The mean visual acuity improved from 0.50 to 0.38. At presentation, eight patients had MH associated with VMT. Closure of the MH with ocriplasmin was achieved in two patients, and six patients underwent pars plana vitrectomy for MH repair. Ten of 23 patients (43.47%) presented with changes in the outer retina reflectivity on SD-OCT after IVO, 4 patients of this group experienced a decrease in visual acuity. In 7 of these 10 patients (70%), VMT release was documented on OCT by Day 30 postinjection compared with 4 of 13 patients (30.76%) without outer retina changes post-IVO. Normalization of the outer retina reflectivity was achieved in all cases. Conclusion: In this case series of VMT/MH patients treated with ocriplasmin, changes in the SD-OCT outer retina reflectivity were relatively common. Within weeks, the outer retinal reflectivity on SD-OCT improved, as did the visual acuity. Further studies to investigate the association between outer retina reflectivity changes with the use of IVO and long-term visual acuity outcomes are warranted.

TREATMENT OF VITREOMACULAR TRACTION WITH INTRAVITREAL PERFLUOROPROPANE (C3F8) INJECTION.

Purpose: To assess the posterior vitreous release rates following a single, office-based intravitreal injection of expansile gas in treating vitreomacular traction. Methods: Thirty eyes of 29 consecutive patients with symptomatic vitreomacular traction received a single, office-based intravitreal injection of up to 0.3 mL of 100% perfluoropropane (C3F8). Results: Overall, vitreomacular traction release occurred in 25 of 30 eyes by the final follow-up visit (83% final release rate); furthermore, 90% (9 of 10 eyes) with diabetes mellitus released, 83% (5 of 6 eyes) with concurrent epiretinal membrane released, and 83% (5 of 6 eyes) previously treated with ocriplasmin released. Vitreomacular traction release occurred overnight in some patients and was documented on spectral domain optical coherence tomography at an average of 13 days (range, 1–62 days). The phakic release rate was 89% (16 of 18 eyes) versus a 75% pseudophakic release rate (9 of 12 eyes) (P = 0.3173). Ellipsoid zone changes on spectral domain optical coherence tomography occurred in 1 of 30 gas-treated eyes. One patient developed pupillary block. Conclusion: Office-based intravitreal injection of C3F8 offers an inexpensive and effective treatment for vitreomacular traction, including for patients who underwent previous ocriplasmin administration and in patients with diabetes mellitus or epiretinal membrane.

Rate of Hypotony Following 25-Gauge Pars Plana Vitrectomy

BACKGROUND AND OBJECTIVE To report the rates of hypotony after 25-gauge vitrectomy. PATIENTS AND METHODS A retrospective review of 111 consecutive cases was performed in patients undergoing transconjunctival 25-gauge pars plans vitrectomy with either air or gas as a tamponade agent. The primary outcome measure was postoperative intraocular pressure less than 5 mm Hg. A Wilcoxon rank-sum test was conducted to determine the statistical significance of continuous variables in association with rates of hypotony. RESULTS The overall incidence of hypotony on postoperative day 1 was found to be 8.1%. The rate of hypotony was 16.7% in uveitis cases and 0% in routine macular surgery. The rate of hypotony in cases in which sutures were used was 41.7%, compared to 4% in cases in which sutures were not used (P = .001). CONCLUSION Hypotony rates were significantly higher after 25-gauge transconjunctival pars plana vitrectomy in uveitis and some other conditions.

Combination Therapies for the Treatment of AMD

Exudative age-related macular degeneration (AMD) is the leading cause of blindness in people over 50 years of age in the Western world.

Large Silicone Droplets After Intravitreal Bevacizumab (avastin)

Purpose: Despite its off-label status, intravitreal bevacizumab is the most commonly used intraocular anti–vascular endothelial growth factor agent. Regulation of compounding pharmacies has recently increased to make compounded pharmaceuticals safer. Despite these changes, a marked increase in symptomatic, large silicone oil droplets following intravitreal bevacizumab injections was noticed. Methods: Retrospective chart review was performed. Within a single private practice, patients who were noted to have large or symptomatic silicone oil bubbles after an intravitreal injection were reviewed. Results: A recent, dramatic increase in the incidence of large or symptomatic silicone oil droplets was noted, with 23 cases noted in the past 5 months, compared with 1 in the previous decade. Patients frequently noted a circular floater consisting of a dark ring surrounding a bright central area immediately following an injection of intravitreal bevacizumab. All bevacizumab injections were from single-piece insulin syringes. B-scan ultrasonography produced a very characteristic reverberation pattern. No inflammation or visual acuity loss was noted because of the droplets; however, some patients were annoyed enough to consider vitrectomy. Conclusion: Patients should be carefully evaluated for this possibility, and the characteristic symptom of a round floater consisting of a dark ring surrounding a bright center, and the prominent reverberation pattern on B-scan ultrasonography may help increase detection. Changes in consent forms and discussion of this possibility are indicated while investigation into the cause of this increased incidence continues, especially if one is administering bevacizumab via the one-piece insulin syringes commonly used by compound pharmacies.

Current Treatment Options for the Management of Vitreomacular Traction

by Dilsher S. Dhoot, MD, and Nathan C. Steinle, MD During the past decade, there has been increasing interest and discussion regarding vitreomacular adhesion (VMA) and traction. This interest has been driven by greater use of optical coherence tomography by community eye care providers, leading to more referrals to retina and the U.S. Food and Drug Administration (FDA)-approval of ocriplasmin (Jetrea; ThromboGenics, Leuven, Belgium), the first treatment for symptomatic VMA in 2012. Usage of Jetrea since FDA approval has dropped to negligible levels given its high side effect profile and cost, as well as the availability of alternate treatments (observation, pneumatic vitreolysis, and small-gauge vitrectomy). Dilsher S. Dhoot, MD, and Nathan C. Steinle, MD, provide us with an overview of the current treatment options for the management of vitreomacular traction. In this article, they will summarize the literature and discuss the pros and cons of each treatment (including observation) for managing patients suffering from this condition. They will also share their research on the use of pneumatic vitreolysis to treat this condition and present an illustrative case. I am certain that the insights and expertise that Drs. Dhoot and Steinle share will be very helpful as we encounter patients with symptomatic vitreomacular traction in our clinics. Posterior vitreous detachment (PVD) is a common occurrence in the aging eye. By the age of 70, a complete PVD is present in at least 50% of individuals.1-3 Although the majority of PVDs occur without complication, a small proportion can be associated with a persistent vitreomacular adhesion (VMA) at the fovea resulting in tractional forces and vitreomacular traction (VMT) (Figure 1). With the increasing adoption of optical coherence tomography (OCT) by community providers, such as optometrists, the identification of VMT in patients has increased, though limited information on the epidemiology of VMT is available in the literature currently. The International Vitreomacular Traction Study Group recently developed an OCTbased classification of vitreomacular interface disorders including VMT. VMA was defined as a perifoveal vitreous cortex detachment from the retinal surface with a macular attachment of the vitreous cortex within a 3-mm radius of the fovea. In VMA, no changes are seen in underlying foveal contour or retinal tissue. VMT was further defined as VMA with associated distortion of the foveal surface, but no full-thickness hole.4 Symptomatic VMT can result in a variety of visual symptoms, though typically metamorphopsia, photopsia, and/or blurred or decreased vision are reported. Current management strategies focus on achieving resolution of traction and include observation, medical therapy, and surgery.

Retinal Infiltrates Secondary To Metastatic Squamous Cell Carcinoma Masquerading As Infectious Retinitis

PURPOSE This report presents a case of metastatic carcinoma to the retina. METHODS Retrospective chart review and systematic literature review. The patient was a 78-year-old man with history of small-cell lung cancer and with the development of metastatic carcinoma to the retina. RESULTS The review of this case and previous literature reveals that the presentation of retinal metastases can occasionally be misinterpreted as infectious retinitis, which can delay the diagnosis of the disease. CONCLUSION Metastatic carcinoma to the retina is a rare condition, which should be considered in patients who are suspected of having infectious retinopathy and who fail to respond to traditional antimicrobial therapies.

Combination Therapy with Ocular Photodynamic Therapy for Age-Related Macular Degeneration

Exudative AMD is the leading cause of blindness in people over 50 years old in the Western world. Choroidal neovascularization found in exudative AMD appears to be a multifactoral process involving inflammatory, vascular, and angiogenic components. Commercially available treatments for exudative AMD primarily target a solitary component of this multifactoral disease. Combining various treatment modalities for exudative AMD targets multiple components of choroidal neovascularization and has the potential for improving efficacy and reducing treatment frequency.