Dilsher S. Dhoot

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.

Evaluation of choroidal thickness in retinitis pigmentosa using enhanced depth imaging optical coherence tomography

Objective To describe the choroidal characteristics of patients with retinitis pigmentosa (RP) using enhanced depth imaging (EDI) and spectral domain (SD) optical coherence tomography (OCT). Purpose To investigate the spectral-domain ocular coherence tomography features of the choroid in patients with RP using EDI. Methods A prospective, case–control study of 21 patients from the Cole Eye Institute with RP imaged using the Spectralis OCT and an EDI protocol. Submacular choroidal thickness measurements were obtained beneath the fovea and at 500 µm intervals for 2.5 mm nasal and temporal to the centre of the fovea. These measurements were compared to choroidal thickness measurements from 25 healthy age-matched controls with similar refractive error range and no clinical evidence of retinal or glaucomatous disease. Statistical analysis was performed to compare choroidal thickness at each location between the two groups and to correlate choroidal thickness with best-corrected visual acuity and central retinal thickness. Results Mean ages were 40.6 years for control patients and 45.1 years for RP patients (p>0.05). Mean choroidal thickness measurements were 245.6±103 µm in RP patients and 337.8.2±109 µm in controls (p<0.0001). There was no correlation between subfoveal choroidal thickness and visual acuity or retinal thickness in the RP patients when compared to the control group. Conclusions Submacular choroidal thickness, as measured by SD–OCT EDI, is significantly reduced in patients with RP, but did not correlate with visual acuity or retinal thickness in RP patients. Further research is needed to understand better the pathophysiological significance of the choroidal alterations present in RP.

Ranibizumab for age-related macular degeneration.

Introduction: Age-related macular degeneration (AMD) is the leading cause of blindness in patients over 50 years in the developed world. The wet form of AMD is responsible for the majority of severe vision loss. VEGF-A is a key component in the development of wet AMD. Ranibizumab is an anti-VEGF agent that has established itself as the gold standard in the treatment of neovascular AMD. Herein, we review the pharmacology, pharmacokinetics, efficacy and safety of ranibizumab. Areas covered: Since its approval in 2006, ranibizumab has revolutionized the treatment of wet AMD. In two pivotal Phase III trials, MARINA and ANCHOR, ranibizumab (0.5 mg) prevented moderate visual loss in 90 and 96% of patients, respectively, and improved vision by 15 letters or more in 33 and 40% of patients, respectively. Fixed monthly dosing regimens were compared with quarterly dosing regimens in PIER and EXCITE studies and support the superiority of fixed monthly dosing. The CATT trial revealed that bevacizumab was not inferior to ranibizumab when dosed monthly. As-needed treatment regimens of ranibizumab were also found to be non-inferior to monthly ranibizumab after 1 year of follow-up. Expert opinion: Ranibizumab has positively altered the treatment of wet AMD and offers hope for millions of patients.

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.

Vascular Endothelial Growth Factor Inhibitors for Diabetic Retinopathy.

The prevalence of diabetes is growing at epidemic rates in the USA. Diabetic retinopathy develops in a large proportion of patients and is a leading cause of blindness worldwide. Systemic management of diabetic retinopathy has included glycemic, hypertension, and lipid control. Local ophthalmic treatment in the form of focal/grid or panretinal laser photocoagulation has been shown to prevent vision loss in diabetic edema and proliferative diabetic retinopathy, respectively. The introduction of anti-vascular endothelial growth factor for diabetic macular edema and retinopathy has provided clinicians with improved clinical outcomes with potentially less damaging effects than laser.

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.

Trans-tamponade optical coherence tomography: postoperative imaging in gas-filled eyes.

Purpose: To investigate the feasibility of trans-tamponade optical coherence tomography and evaluate factors contributing to image quality and acquisition success. Methods: Retrospective case series of eyes receiving Postoperative Day 1 optical coherence tomography imaging after vitrectomy and gas tamponade. The quality of the scans was graded by three independent expert readers. Clinical and surgical variables were recorded and correlated with scan quality. Results: Eighty eyes were included in the study. An image quality classification scheme was developed (0–4, 0 = no image and 4 = comparable quality to trans-fluid optical coherence tomography). In 51 scans (64%), visualization of the inner retina and retinal pigment epithelium was achieved (Grades 2–4) but with variable image quality of the retinal layers. Twenty-nine scans (36%) achieved visualization of all retinal layers (Grades 3–4). Only 9 scans (11%) were of comparable quality to fluid-filled eyes (Grade 4). Pseudophakia (P = 0.0001), shorter operative times (P = 0.007), and macular surgery (P = 0.002) correlated with scan quality. An optimum scan protocol was developed to facilitate maximum quality images. Conclusion: Successful trans-tamponade optical coherence tomography through gas on Postoperative Day 1 is possible but significant variability exists in scan quality.

Pediatric infectious posterior uveitis.

Uveitis represents a collection of inflammatory diseases of the eye. It occurs at a prevalence of 93 per 100,000 in adults and is a common cause of blindness. The annual incidence ranges from 26 to 102 per 100,000. Uveitis in the pediatric population is less common than adults, occurring in 30 cases per 100,000, with an incidence of 4.3 to 6.9 per 100,000. In most tertiary uveitis clinics, children account for 5% to 10% of all cases observed. Although the majority of cases of uveitis in children are noninfectious, infectious etiologies are responsible for up to 13% of all pediatric uveitis cases. It is important to recognize the more common cases of infectious uveitis in children as the use of immunosuppressive therapy in these cases can lead to poor visual outcomes. Here, we present relatively common and uncommon causes of posterior infectious uveitis in children. Autoimmune etiologies of pediatric uveitis are presented in a separate chapter in this series.

When and How to Incorporate Steroids for Persistent Diabetic Macular Edema: A Discussion of Real-World Treatment Optimization Strategies

In the United States, diabetic macular edema (DME) is the leading cause of vision loss among people with diabetic retinopathy. Despite the availability of different therapies for DME, up to half of patients with DME show some persistent edema after anti-vascular endothelial growth factor (VEGF) treatment alone, leaving these patients at high risk for vision loss. However, dosing in a similar fashion to that of pivotal anti-VEGF trials is difficult because of real-life challenges faced in clinical practice. This is particularly true for DME, in that the frequency and burden of anti-VEGF injections are a major challenge to patient care. Research evaluating anti-VEGF therapies has shaped the treatment paradigms for patients with DME, and similar benefits have also been noted in clinical trials evaluating the use of intravitreal steroids. Treatment with a long-term intravitreal corticosteroid, which requires fewer injections than treatment with most short-acting therapies, has been found to reduce inflammation and improve vision in a percentage of patients. This roundtable discussion, which took place during the 2018 annual meeting of the Vit-Buckle Society, reviews the current treatment paradigms for DME and evaluates how to customize and optimize treatment strategies geared toward individualized patient care. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:S5-S15.].