Sustained-release fluocinolone acetonide intravitreal insert for macular edema: clinical pharmacology and safety evaluation

Introduction: Inflammation plays a key role in the pathological processes leading to macular edema. Sustained release, low-dose intraocular corticosteroid delivery devices provide long-term anti-inflammatory therapy. Recently, a novel fluocinolone acetonide intravitreal insert (FAi, Iluvien), has been introduced with promising long-term results in the treatment of macular edema.

Areas covered: An extensive review of the literature in the English language was performed to provide comprehensive information on the pharmacological properties of FAi and its safety and efficacy data from various multi-center randomized clinical trials.

Expert opinion: The FAc, Retisert is a sustained-release device that is surgically implanted in the vitreous and has been approved by the US FDA for the treatment of non-infectious intermediate, posterior or panuveitis. FAi was developed after FAc and is an intravitreal corticosteroid delivery system that allows controlled release of therapeutic levels of fluocinolone acetonide (FA). Initial efficacy and safety data suggest that this delivery system maintains clinical effectiveness for up to 3 years after a single delivery of the device. This second-generation fluocinolone delivery device has shown superior safety results in clinical trials compared to the previous version of the higher dose FAc (0.59 mg). Sustained delivery preparations may help to reduce the treatment burden and its associated risks by decreasing the frequency of intravitreal injections. However, much needs to be learnt from additional clinical trials, post-marketing surveillance and results of extension studies. Concerns of intravitreal corticosteroids, such as cataract and increase in intraocular pressure, remain major challenges for this therapeutic strategy.     

Intravitreal dexamethasone implant Ozurdex in the treatment of diabetic macular edema in patients not previously treated with any intravitreal drug: a prospective 12-month follow-up study

Abstract

Objective: To evaluate the mid-long-term efficacy and safety of the dexamethasone intravitreal (DEX) implant (Ozurdex¹) in naïve patients with diabetic macular edema (DME).

Methods: Prospective and single-center study conducted on consecutive patients with a diagnosis of DME, who received a DEX implant and were followed up for at least 12?months. The main outcomes measurements were the mean change in best corrected visual acuity (BCVA) and in foveal thickness (FT) as compared to the baseline values.

Results: Of the 84 screened patients 50 were included in the study. The BCVA significantly improved from 52.4 (20.4) letters at baseline to 62.6 (15.6), 61.2 (18.4), 61.6 (18.6), 60.6 (19.0), and 60.6 (18.8) at 2, 4, 6, 12?months and end of follow-up period, respectively (repeated measures ANOVA and the Greenhouse-Geisser correction; p?=?.0008). At the end of the follow-up period, a gain of BCVA of ≥5, ≥10, and ≥15 letters were observed in 26 (52.0%), 18 (36.0%), and 16 (32.0%) patients, respectively. The mean FT was significantly reduced from 446.0 (139.9) µm at baseline to 327.2 (103.6) at the end of follow-up (repeated measures ANOVA and the Greenhouse-Geisser correction; p?=?.0008). During the study follow-up, the patients receive a mean of 3.4 (2.9–3.9) implants. Of the 32 phakic eyes at baseline, 17 (53.1%) either developed new lens opacity or progression of an existing opacity.

Conclusion: In eyes with DME not previously treated with intravitreal drugs, DEX implants provide meaningful functional and anatomical benefits, and these results are sustained mid–long-term.     

Post-operative refractory cystoid macular edema in a vitrectomized eye treated with slow-release dexamethasone implant (Ozurdex)

Introduction: The use of a slow-release dexamethasone implant (Ozurdex) for the treatment of post-operative macular edema (ME) in a vitrectomized eye has never been used before. We herein report a case of a 70-year-old woman with post-vitrectomy ME refractory to topical, sub-tenon’s and intravitreal steroid administration that responded well to the implantation of a slow-release dexamethasone implant (Ozurdex) in a previously vitrectomized eye.

Methods: Interventional case presentation.

Results: One week post-implantation, the central retinal thickness was reduced to 383?μm from 640?μm and the best corrected visual acuity (BCVA) improved to 6/36 from counting fingers (CF). At six months’ follow-up visit, the improvement of the ME was sustained as indicated by the optical coherence tomography (OCT) measurements and the BCVA remained stable. No serious topical or systemic adverse events were observed from the implantation of Ozurdex in the vitrectomized eye.

Conclusion: The use of Ozurdex in our case resulted in rapid improvement of the post-operative resistant ME. To the best of our knowledge, this is the first report in the literature demonstrating the use of the slow-release dexamethasone implant (Ozurdex) to treat post-operative ME in a vitrectomized eye.     

Nonbiological pharmacotherapies for the treatment of diabetic macular edema

Introduction: During the past decade, there have been significant advances in the pharmacotherapies for the treatment of diabetic macular edema (DME). Among the presently available treatment options, anti-vascular endothelial growth factors (anti-VEGF) agents are the most favored agents due to their efficacy and safety. The index review focuses on nonbiological therapies that have entered in phase 3 clinical trials for DME.

Areas covered: An extensive review of the literature was performed to identify various nonbiological immunotherapies i.e., drugs other than ‘-mAbs’ (monoclonal antibodies including anti-VEGF agents), ‘-mibs’ (proteasome inhibitors), ‘-NAbs’ (nanoparticle albumin-bound), and ‘-nibs’ (small molecule inhibitor/tyrosine kinase inhibitors), among others. Extended-release low-dose corticosteroid devices have been recently approved for the treatment of DME. Other compounds such as non-steroidal anti-inflammatory drugs, antibody mimetic proteins, nonbiological growth factor inhibitors, and inhibitors of protein kinase C have been described.

Expert opinion: A number of therapies are under development for the pharmacological management of DME. Due to the rising healthcare costs associated with anti-VEGF agents, a number of alternate treatment options have been explored recently. Some of these agents have reached phase 3 in clinical trials and appear to have a promising role in the management of DME. As further research is conducted, the role of each individual agent will become more defined, alone or in combination therapy.     

Upcoming therapeutic advances in diabetic macular edema: an intravitreal dexamethasone drug delivery system

Introduction: Diabetes mellitus, through its ophthalmic complications diabetic retinopathy and diabetic macular edema (DME), is a leading cause of vision loss in industrialized countries.

Areas covered: This review covers laser treatment, which is a standard treatment strategy that has proven efficacy and safety through large clinical trials in DME. Several intravitreal drug applications currently being investigated are also discussed.

Expert opinion: First results suggest that the administration of anti-VEGF compounds is effective for DME. However, frequent injections may compromise safety. In order to enhance patient compliance, sustained delivery systems are being evaluated as potential treatment approaches. So far, only steroids have been included as active in such non-biodegradable or biodegradable delivery systems. Non-biodegradable systems are more complicated to administer as surgery is required and they need to be retrieved at the end of treatment. Also, in some cases safety issues have arisen, especially around intraocular pressure control. A new biodegradable dexamethasone delivery system seems to show promising efficacy results in addition to a more favorable safety profile, which will potentially improve patient compliance. All new therapeutic approaches, alone and in combination, will need to demonstrate their efficacy and safety in DME in future trials.     

Fluocinolone acetonide for the treatment of diabetic macular edema

In addition to VEGF inhibitors such as ranibizumab, aflibercept or bevacizumab, clinical and experimental investigations have revealed the great potential of steroids in the treatment of DME. At present two intravitreal steroid inserts are approved for the treatment of DME containing either dexamethasone or fluocinolone acetat (FA) as a pharmacological compound. The non degradable intravitreal FA insert releases 0.2 µg FA per day (Iluvien, Alimera Sciences). Clinical phase III studies have demonstrated the beneficial effect of the FA insert to last up to three years, especially in patients with a prolonged history of DME of at least three years at the initiation of therapy. While the treatment appears to be well tolerated over all, side effects such as cataract formation in nearly all treated phakic patients and raise of intraocular pressure need to be discussed with the patients as potential complications of the treatment.     

Intravitreal bevacizumab and dexamethasone implant for treatment of chronic diabetic macular edema

Objective: To evaluate anatomical and functional outcomes of intraviteal bevacizumab (IVB) in patients with chronic diabetic macular edema (DME), and the effectivity and safety of dexamethasone implant in those unresponsive to regular IVB treatment. Methods: Thirty-five eyes of 35 patients (16 male and 19 female) with chronic DME (central foveal thickness (CFT) >?275?μm, duration >?6 months) received three injections of 2.5?mg IVB with six-week intervals. At 18 weeks, dexamethasone implant was applied to patients unresponsive to IVB. Main outcomes were the change in best corrected visual acuity (BCVA), CFT and ocular and systemic adverse effects for both drugs. The patients responsive to IVB were followed up for 36 weeks and those patients receiving dexamethasone implant were followed up for 24 weeks postoperatively. Results: At 18 weeks, the mean BCVA (0.68?±?0.40 logMAR, p?=?0.45) and CFT (453?±?169?μm, p?=?0.58) did not show any significant change compared to baseline (0.74?±?0.42 logMAR and 521?±?151?μm, respectively). In 20 patients (%57.1) responsive to IVB, the CFT was significantly improved from 12 to 36 weeks with the mean value of 295?±?42 μ (p?=?0.01). However, no significant difference was observed for BCVA during this period (p?=?0.17). Dexamethasone was implanted in 15 eyes (42.8%) unresponsive to IVB at 18 weeks. Statistically significant improvements were observed in BCVA (at postoperative 4 and 12 weeks) and CFT (at postoperative 4, 12 and 24 weeks). In addition, both parameters significantly worsened at 24 weeks compared to 12 weeks (p?<?0.001 and p?=?0.01, respectively). Conclusions: Patients with chronic DME should be followed in accordance with a fixed treatment protocol combining anti-VEGF and steroid treatments.     

曲安奈德治疗重度糖尿病黄斑水肿的临床观察

目的研究玻璃体腔内注射曲安奈德(TA)治疗重度糖尿病黄斑水肿的有效性。方法对36例(42眼)重度糖尿病黄斑水肿的患者,行玻璃体腔内注射TA(进口)(4mg/0.1ml)的治疗方法。观察治疗前后的四个指标:最佳矫正视力、眼压、眼底荧光血管造影(FFA)、OCT检测黄斑中心凹厚度。随访时间6～12个月(平均9个月)。结果本组病例36例(42眼),年龄45～70岁(平均57岁),FFA检查治疗前黄斑荧光渗漏明显,治疗后渗漏明显减轻;OCT检测黄斑中心凹厚度,治疗前平均(579.5±65)μm,治疗随访6个月后平均(279±78)μm,差异有统计学意义(P<0.05);最佳矫正视力范围治疗前为0.01～0.2,平均0.1,治疗后为0.2～0.4,平均0.3,差异有统计学意义(P>0.05);所有患者眼压都有升高,升高值8.0～20.0mmHg(平均14.0mmHg),7例(7眼)超过正常眼压范围,经治疗,眼压控制,没有严重并发症发生。结论玻璃体腔注射TA是治疗重度糖尿病黄斑水肿的有效方法,患者的视力有轻度提高,治疗后患者FFA,黄斑区荧光素渗漏明显减轻,OCT检查,证实黄斑厚度明显减小。     

Impact of intravitreal triamcinolone acetonide versus intravitreal bevacizumab on retrobulbar hemodynamic in patients with diabetic macular edema

Purpose: To evaluate and compare retrobulbar hemodynamic changes measured with color Doppler imaging (CDI) in diabetic patients receiving intravitreal triamcinolone acetonide (IVTA) versus bevacizumab.

Methods: Patients with diffuse diabetic macular edema were assessed prospectively by CDI following intravitreal injection of triamcinolone acetonide (group I, 12 eyes) versus bevacizumab (group II, 14 eyes). CDI was used to measure the peak systolic velocity (PSV), end diastolic velocity (EDV) and the resistive index (RI) of the central retinal artery (CRA), ophthalmic artery (OA) and posterior ciliary arteries (PCA) one day preoperatively and one week postoperatively.

Results: In group I, EDV of OA and CRA decreased significantly (p?=?0.007 and 0.018, respectively). The PSV and RI of PCA decreased significantly (p?=?0.035 and 0.002, respectively). In group II, both the PSV and EDV of the CRA decreased significantly (p?=?0.000). Comparing the percentage of change in both groups, PSV of the CRA decreased significantly in group II (p?=?0.034), while IVTA has more significant effect on the ophthalmic artery hemodynamic parameters as EDV decreased and RI increased significantly (p?=?0.045 and 0.043, respectively)

Conclusion: Intravitreal injections of triamcinolone acetonide and bevacizumab have a significant effect on the ocular hemodynamic. The effect of bevacizumab is statistically significant on the PSV of CRA compared to IVTA.     

玻璃体内注射阿柏西普治疗顽固性糖尿病黄斑水肿的临床疗效分析

目的 探究玻璃体内注射阿柏西普治疗顽固性糖尿病黄斑水肿(DME)的临床疗效.方法 70例顽固性DME患者,随机分为对照组及观察组,每组35例.对照组玻璃体内注射雷珠单抗,观察组玻璃体内注射阿柏西普.对比两组黄斑中心凹视网膜厚度(CFT)、最佳矫正视力(BCVA)、眼压及不良反应发生情况.结果 术后1、2个月,两组CFT...     

Pharmacotherapeutic management of macular edema in diabetic subjects undergoing cataract surgery

ABSTRACT

Introduction: Cataracts and diabetes are widespread pathologies that are of growing concern to the global population. In diabetic patients who have had cataract surgery, the worsening of preexisting diabetic macular edema or occurrence of pseudophakic cystoid macular edema are common causes of visual impairment even with the most advanced surgical techniques available today for phacoemulsification.

Areas covered: In this review, the authors assess the available literature to evaluate and compare different drugs, with the aim of establishing the best pharmacological strategies for the prevention and treatment of macular edema in diabetic patients undergoing cataract surgery.

Expert opinion: Guidelines for the optimal management of diabetic macular edema in conjunction with cataract surgery or treatment of pseudophakic cystoid macular edema in diabetic patients are still lacking. To treat these conditions, clinicians need to understand the pharmacokinetics, posology, and efficacy of available drugs: topical non-steroidal anti-inflammatory drugs (NSAIDs), intravitreal anti-vascular endothelial growth factors (VEGFs), and both topical and intravitreal steroids. Diabetic patients undergoing cataract surgery should receive topical NSAIDs to prevent pseudophakic cystoid macular edema. Intravitreal anti-VEGFs and steroids, in association with cataract surgery, are indicated for patients with preexisting diabetic macular edema or those at high risk of macular edema after surgery.     

Fluocinolone acetonide for the treatment of diabetic macular edema

Introduction: Fluocinolone acetonide intravitreal implant is a non-erodible implant approved for the treatment of diabetic macular edema (DME) insufficiently responsive to available therapies.

Areas covered: The injectable intravitreal implant releases fluocinolone acetonide at an average rate of 0.2 µg/day for at least 36 months. The two pooled pivotal FAME trials showed that, in patients with DME previously treated with laser photocoagulation, fluocinolone acetonide intravitreal implant was more beneficial than sham injection when looking at the proportion of patients with an improvement from baseline in visual acuity of more than 15 letters at 24 months and at 36 months. Cataract (82%) and intraocular pressure (IOP) elevation (37%) were the most common adverse events. Raised IOP was mostly treated with IOP-lowering medications, with <5% of eyes requiring incisional IOP-lowering surgery. FAME trial program results are confirmed by a series of real-world studies in eyes with chronic/recalcitrant DME.

Expert opinion: data indicate that fluocinolone acetonide intravitreal implant is a useful second-line option for the treatment of DME.     

球后注射曲安奈德联合激光光凝治疗糖尿病弥漫性黄斑水肿的疗效观察

目的 观察曲安奈德（TA）球后注射联合格栅样光凝（MLG）治疗糖尿病性弥漫性黄斑水肿（DME）的疗效.方法 以50眼糖尿病性DME为研究对象,30眼给予球后注射TA联合MLG,20眼给予单纯MLG,治疗6个月内,观察患眼视力、黄斑水肿以及黄斑中心凹视网膜厚度.结果 TA联合MLG组患者视力提高21眼,视力不变6眼,视力下降3眼;黄斑中心凹区视网膜厚度治疗前为（598.62±198.58） μm,治疗6个月后（307.51±101.21） μm.MLG组视力提高2眼,视力不变10眼,视力下降8眼;黄斑中心凹区视网膜厚度治疗前为（574.73±187.12） μm,治疗6个月后（369.12±112.20） μm.两治疗组间治疗后有统计学差异.结论 TA球后注射联合MLG治疗糖尿病DME可改善视力、促进黄斑水肿吸收.     

胃漂浮片的研究进展

综述了胃漂浮片的释药机理、适用性、处方组成及制备中的关键影响因素等方面的内容，并列举一些新型剂型实例；综述。     

Current concepts of pharmacotherapy of diabetic macular edema

ABSTRACT

Introduction: Diabetic macular edema (DME) is a sight threatening disease and a major cause for blindness for people in working age. The pathogenesis is multifactorial and complex. The pharmacotherapy of DME addresses both the inhibition of vascular endothelial growth factor (VEGF) by the intravitreal injection of VEGF inhibitors and inflammatory processes by the intravitreal application of steroids. Several trials have been published reporting on the efficacy and safety of these treatments.

Areas covered: This review discusses original research articles including basic science and clinical studies as well as review articles focusing on the role of inflammation and VEGF expression in DME. It discusses newly published clinical trials on intravitreal pharmacotherapy for DME. The literature was searched using Medline/PubMed and was selected given its relevance for the topic to be discussed.

Expert opinion: Our knowledge regarding the pathophysiology of diabetic macular edema has significantly increased. Some of these insights have been successfully transferred into current treatment strategies already including VEGF suppression or anti-inflammatory treatments using steroids. The identification of additional pathophysiological aspects and their relevance as potential treatment targets will be a future challenge in the treatment of DME. A better knowledge on the complex pathophysiology will also help to establish combination strategies.     

康柏西普与雷珠单抗治疗视网膜中央静脉阻塞继发黄斑水肿的疗效及安全性分析

目的 比较康柏西普与雷珠单抗治疗视网膜中央静脉阻塞（central retinal vein occlusion,CRVO）继发黄斑水肿的效果和安全性。方法 将陕西省杨凌示范区医院自2015年6月-2017年1月纳入的CRVO继发黄斑水肿患者102例作为研究对象,随机分为两组,即使用康柏西普治疗的A组50例（50眼）,使用雷珠单抗治疗的B组52例（52眼）,观察治疗后1、3、6个月时患者视力恢复情况和黄斑部视网膜厚度变化情况,评价不同药物的治疗效果和安全性。结果 治疗6个月后A组患者视力提高率（52.00%）高于B组（30.77%）,差异具有统计学意义（P<0.05）;两组患者的黄斑部视网膜厚度的改善A组优于B组,且各个复诊时间点比较,差异均具有统计学意义（P<0.05）。两组不良反应发生率分别为8.00%和11.54%,差异无统计学意义。结论 康柏西普治疗CRVO继发黄斑水肿的临床效果优于雷珠单抗,但二者的安全性差异不显著,有待于进一步长期大样本研究证实。     

A safety evaluation of ranibizumab in the treatment of age-related macular degeneration

Introduction: The use of intravitreal ranibizumab has transformed the outcomes for thousands of patients with wet age related macular degeneration (AMD), which is the leading cause of blindness in developed countries. Prior to its introduction, most patients with wet AMD would rapidly lose central vision. The use of intravitreal ranibizumab has been shown to reduce certifiable visual loss by about a half. Current treatment regimens with ranibizumab in wet AMD require multiple injections over several years and so it is highly relevant to review the safety record of this important drug.

Areas covered: This review considers the important ocular and systemic adverse events (AE) that have been reported in the literature, particularly in the context of the pivotal clinical trials that have been performed. It also reviews the safety of other anti-VEGF drugs that are used in wet AMD, namely bevacizumab and aflibercept, and compares these drugs with ranibizumab.

Expert opinion: Overall, intravitreal ranibizumab can be considered a safe and highly effective drug for patients with wet AMD. However recent concerns about retinal thinning following ranibizumab therapy, possible systemic AE associated with all anti-VEGF drugs and the occurrence of complications relating to drug preparation and delivery must be considered.     

2nd Ophthalmic Drug Development and Delivery Summit

The Second Annual Ophthalmic Drug Development and Delivery Summit was held on 19 – 20 September 2006 in San Diego, CA, US. The 2-day symposium, having a highly focused theme, was packed with cutting-edge science, insightful overviews and networking opportunities. With a total of 11 recognized specialists presenting reviews and recent results in the advancement of ocular drug development and delivery, the invited expert speaking faculty presented the latest preclinical and clinical developments in novel ophthalmic therapies and drug delivery technology. The talks included various case studies from primary investigators and pharmaceutical companies touching upon key topics: updates on current clinical trials, study design issues, sustained delivery to the eye, views of the vitreous space as a drug reservoir, new developments in dry and wet age-related macular degeneration and diabetic retinopathy, formulation for optimal drug delivery, differences and similarities in developing drugs for the eye compared with other targets, pharmacokinetics, novel ocular delivery methods and devices, delivery of proteins and peptides, focal drug delivery, non-invasive drug delivery to the eye, neuroprotection challenges, in vitro and in vivo models for glaucoma and angiogenesis for early efficacy estimation, and toxicology. Overall, the 2-day annual symposium continues to grow as an efficient platform for fostering discussion on a range of scientific topics and challenges and avenues for building collaborative partnerships in ophthalmic drug development.     

Strategies for modifying drug residence time and ocular bioavailability to decrease treatment frequency for back of the eye diseases

Introduction: Treating posterior eye diseases has become a major area of focus for pharmaceutical and biotechnology companies. Current standard of care for treating posterior eye diseases relies on administration via intravitreal injection. Although effective, this is not without complications and there is great incentive to develop longer-acting therapeutics and/or sustained release delivery systems. Here, we present an overview of emerging technologies for delivery of biologics to the back of the eye.

Areas covered: Posterior eye diseases, intravitreal injection, age-related macular degeneration, anti-VEGF, ocular pharmacokinetics, novel technologies to extend half-life, in vivo models, translation to the clinic, and hurdles to effective patient care.

Expert opinion: Posterior eye diseases are a worldwide public health issue. Although anti-VEGF molecules represent a major advance for treating diseases involving choroidal neovascularization, frequent injection can be burdensome for patients and clinicians. There is a need for effective and patient-friendly treatments for posterior eye diseases. Many technologies that enable long-acting delivery to the back of the eye are being evaluated. However, successful development of novel therapies and delivery technologies is hampered by a multitude of factors, including patient education, translatability of in vitro/in vivo preclinical data to the clinic, and regulatory challenges associated with novel technologies.     

Surfactant-polymer Nanoparticles: A Novel Platform for Sustained and Enhanced Cellular Delivery of Water-soluble Molecules

Purpose Nanoparticles, drug carriers in the sub-micron size range, can enhance the therapeutic efficacy of encapsulated drug by increasing and sustaining the delivery of the drug inside the cell. However, the use of nanoparticles for small molecular weight, water-soluble drugs has been limited by poor drug encapsulation efficiency and rapid release of the encapsulated drug. Here we report enhanced cellular delivery of water-soluble molecules using novel Aerosol OT™ (AOT)-alginate nanoparticles recently developed in our laboratory. Materials and Methods AOT-alginate nanoparticles were formulated using emulsion-crosslinking technology. Rhodamine and doxorubicin were used as model water-soluble molecules. Kinetics and mechanism of nanoparticle-mediated cellular drug delivery and therapeutic efficacy of nanoparticle-encapsulated doxorubicin were evaluated in two model breast cancer cell lines. Results AOT-alginate nanoparticles demonstrated sustained release of doxorubicin over a 15-day period in vitro. Cell culture studies indicated that nanoparticles enhanced the cellular delivery of rhodamine by about two–tenfold compared to drug in solution. Nanoparticle uptake into cells was dose-, time- and energy-dependent. Treatment with nanoparticles resulted in significantly higher cellular retention of drug than treatment with drug in solution. Cytotoxicity studies demonstrated that doxorubicin in nanoparticles resulted in significantly higher and more sustained cytotoxicity than drug in solution. Conclusions AOT-alginate nanoparticles significantly enhance the cellular delivery of basic, water-soluble drugs. This translates into enhanced therapeutic efficacy for drugs like doxorubicin that have intracellular site of action. Based on these results, AOT-alginate nanoparticles appear to be suitable carriers for enhanced and sustained cellular delivery of basic, water-soluble drugs.