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Pharmacokinetic Simulations of Intravitreal Biologicals: Aspects of Drug Delivery to the Posterior and Anterior Segments
摘要： Biologicals are important ocular drugs that are be delivered using monthly and bimonthly intravitreal injections to treat retinal diseases, such as age-related macular degeneration. Long acting delivery systems are needed for prolongation of their dosing interval. Intravitreal biologicals are eliminated from the eye via the aqueous humor outflow. Thus, the anterior and posterior segments are exposed to the drug. We utilized a kinetic simulation model to estimate protein drug concentrations in the vitreous and aqueous humor after bolus injection and controlled release administration to the vitreous. The simulations predicted accurately the experimental levels of 5 biologicals in the vitreous and aqueous humor. The good match between the simulations and experimental data demonstrated almost complete anterior segment bioavailability, and major dose sparing with ocular controlled release systems. Overall, the model is a useful tool in the design of intraocular delivery of biologicals.
关键词： aflibercept,ocular drug delivery,ranibizumab,intravitreal injection,controlled release,bevacizumab
更新于2025-09-23 15:22:29
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Baseline characteristics associated with early visual acuity gains after ranibizumab treatment for retinal vein occlusion
摘要： Background: To identify baseline patient characteristics associated with early clinically significant visual acuity (VA) improvements within 3 months of treatment initiation in ranibizumab-treated patients with retinal vein occlusion (RVO) in the SHORE study. Methods: Post hoc analysis of baseline patient characteristics in the randomized, open-label, vision examiner–masked SHORE phase 4 study that compared monthly versus pro re nata dosing of ranibizumab in patients with branch and central RVO. Patients who enrolled in SHORE fulfilled eligibility criteria per protocol (N = 202). SHORE data were retrospectively analyzed to identify baseline patient characteristics associated with early clinically significant improvements in VA, defined as improvement to a Snellen equivalent of 20/40 or better vision (≥ 69 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) or an increase in best-corrected VA (BCVA) of 15 or more ETDRS letters from baseline within 3 months of treatment initiation. Main outcome measures were BCVA gain of 15 or more ETDRS letters from baseline, Snellen equivalent of 20/40 or better vision, and baseline factors associated with early clinically significant improvement in BCVA. Results: The median time for patients to achieve a BCVA of 20/40 or better was 59 days and the median time for patients to gain 15 or more ETDRS letters was 63 days. Better baseline BCVA (> 50 ETDRS letters/Snellen equivalent ≥ 20/100), greater baseline total macular volume (> 9.99 mm3), and presence of subretinal fluid at baseline were all associated with early improvement to 20/40 or better vision (ETDRS equivalent ≥ 69 letters; P < .0001, P = .02, and P = .03, respectively). Conclusions: This retrospective analysis found that better BCVA, greater total macular volume, and presence of subretinal fluid at baseline were associated with more rapid vision gains. Clinicians may find these helpful when considering the likelihood of achieving early clinically significant VA improvements with ranibizumab in patients with RVO.
关键词： Ranibizumab,Branch retinal vein occlusion,Central retinal vein occlusion,CRVO,BRVO,Retinal vein occlusion,Anti-VEGF,RVO
更新于2025-09-23 15:22:29
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Critical evaluation of the off-label indication and of the risks associated to the use of multi-dose vials on the treatment of age-related macular degeneration
摘要： Age-related macular degeneration (AMD) is an ocular inflammatory diseases treated mainly by means of a bevacizumab (Avastin?) or ranibizumab (Lucentis?) intravitreal injection. Among these drugs, only ranibizumab has a specific therapeutic indication for AMD. Considering that, the off-label use on ophthalmic therapy seems to become a rule when it should be an exception. Furthermore, bevacizumab presentation consists of multi-dose vials although it does not contain preservatives in its formula. The current literature review aimed at assessing the risks for the patient related to the use of off-label indication and multi-dose vials on AMD treatment. Considering this, the proposal related to the Brazilian Public Consultation no.10, dated September 12, 2012, which proposes the Clinical Protocol and Therapeutic Guidelines for AMD treatment, was evaluated. This systematic review allowed to conclude that the bevacizumab off-label indication results in increased risks for the patient when compared to the product with specific therapeutic indication for AMD treatment (ranibizumab), especially referring to the significant raise in the adverse events. The risks for the patient related to the multi-dose vial use, referring to the microbiological stability and dose precision, were also made clear.
关键词： Multi-dose vials/patients risks,Ranibizumab/intravitreal injection,Age-related macular degeneration/treatment,Off-label indication/patients risks,Ophthalmic therapy/off-label use,Bevacizumab/intravitreal injection
更新于2025-09-23 15:22:29
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Multimodal imaging based biomarkers predictive of early and late response to anti-VEGFs during the first year of treatment for neovascular age-related macular degeneration
摘要： Purpose. — To evaluate baseline predictive markers of early and late anatomical response to anti-vascular endothelial growth factor (anti-VEGF) treatment in patients with neovascular age-related macular degeneration (nAMD). Methods. — The records of the nAMD patients who underwent intravitreal ranibizumab or aflibercept treatment, received the 3 monthly loading doses, and completed a follow-up period of 12 months were included retrospectively. The anatomical treatment response at month 3 (early) and between month 3 and 12 (late) was classified as good, intermediate or poor. Baseline demographic, fluorescein angiography, and optical coherence tomography findings were compared among the three groups. Results. — One hundred and ten eyes (74.3%) showed good, 18 (12.2%) showed intermediate and 20 (13.5%) showed poor anatomical response at month 3, and 114 eyes (77.0%) showed good, 27 (18.2%) showed intermediate and 7 (4.7%) showed poor anatomical response between month 3 and month 12. Of the evaluated parameters, drug type (better in aflibercept), showed a statistically significant difference in regards to anatomical outcomes at both the early and late periods (P = 0.02 and P = 0.03). The greatest linear dimension of choroidal neovascularization (CNV) and presence of peaked pigment epithelial detachment (PED) were important factors for early anatomical anti-VEGF treatment response. Conclusion. — Larger CNV and the presence of a peaked PED appeared to be associated with a good early response, and the drug type seemed to be associated with both early and late poor anatomical response of anti-VEGF treatment in nAMD patients. Aflibercept appears to be more effective than ranibizumab in regards to the percentage of patients with better anatomical response in both the early and late treatment periods.
关键词： Optical coherence tomography,Ranibizumab,Age-related macular degeneration,Aflibercept,Fluorescein angiography
更新于2025-09-23 15:22:29
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Efficacy of aflibercept on exudative age-related macular degeneration in patients exhibiting complete ranibizumab resistance and tachyphylaxis
摘要： Purpose: The present study compared the efficacy of aflibercept for neovascular age-related macular degeneration (NV-AMD) in patients with complete ranibizumab resistance and tachyphylaxis. Methods: Forty-four eyes of 38 neovascular age-related macular degeneration patients were evaluated. Eyes were divided into a complete resistance group (n=23 eyes) and tachyphylaxis group (n=21 eyes). Results: After three injections, eight (38.1%) patients in the tachyphylaxis group and nine (39.1%) in the complete resistance group presented with macular dryness. After the first injection of aflibercept, the mean visual acuity improved significantly in the tachyphylaxis group (p=0.018) but remained unchanged in the complete resistance group (p=0.37). There was a non-significant trend towards improved mean visual acuity in both groups after the second and third injections relative to the acuity at the final visit for ranibizumab treatment. In the tachyphylaxis group, the presence of subfoveal pigmented epithelium detachment (PED) decreased significantly after intravitreal aflibercept treatment. Conclusions: Although treatment with aflibercept yielded generally positive anatomical results in both groups, no significant increase in visual acuity was achieved.
关键词： Tachyphylaxis,Ranibizumab,Angiogenesis inhibitors,Vascular endothelial growth factor A,Macular degeneration
更新于2025-09-23 15:21:21
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Comparison of OCT angiography in children with a history of intravitreal injection of ranibizumab versus laser photocoagulation for retinopathy of prematurity
摘要： Purpose To compare the foveal microvascular structure characteristics in children with a history of intravitreal injection of ranibizumab (IVR) versus laser photocoagulation (LP) for retinopathy of prematurity by optical coherence tomography angiography (OCTA). Methods In this cross- sectional study, a total of 17 children (28 eyes) underwent IVR and 20 children (37 eyes) underwent LP were recruited. The age of doing OCTA examination of the two groups are 5.4±1.1 years and 6.3±1.8 years, respectively (p=0.07). Spectral- domain OCTA was performed for all the eyes with a scan size of 3×3 mm. The data of the superficial retinal layer were analysed. The foveal avascular zone (FAZ) and vessel density (including vessel length density (VLD) and perfusion density (PD)) were measured using the software of OCTA (Cirrus AngioPlex 5000, Carl Zeiss, Meditec, Dubin, California, USA). The central foveal thicknesses (CFT) were measured by cross- sectional OCT. results In the central fovea, the retinal VLD and PD of patients with IVR were 13.82±2.99 mm/ mm2 and 0.25±0.05 mm2/mm2, respectively, which were significantly lower than those of the LP group (15.64±2.71 mm/mm2 and 0.28±0.05 mm2/mm2, p=0.01 and p=0.006). The FAZ area of patients with IVR and LP were 0.13±0.09 mm2 and 0.09±0.07 mm2, respectively (p=0.048). The CFT of patients with IVR and LP were 200.7±16.7 μm and 220.9±22.7 μm, respectively (p<0.01). The logarithm of the minimal angle of resolution best- corrected visual acuity of patients with IVR and LP were 0.2±0.1 and 0.1±0.1, respectively (p=0.01). There was no significant difference in the parafoveal and foveal VLD and PD, FAZ morphological index and spherical equivalent refraction (SER) between the two groups. Conclusion The IVR might contribute to microvascular changes in the macular zone, such as reducing the central foveal VLD and PD, while the LP might contribute to microstructural changes, such as smaller FAZ and thicker CFT.
关键词： intravitreal injection of ranibizumab,foveal microvascular structure,OCT angiography,laser photocoagulation,retinopathy of prematurity
更新于2025-09-23 15:21:01
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Statement of the BVA, the DOG, and the RG on treatment of choroidal neovascularization in diseases other than neovascular age-related macular degeneration; Stellungnahme des BVA, der DOG und der RG zur Therapie chorioidaler Neovaskularisationen bei anderen Erkrankungen als der neovaskul?ren altersabh?ngigen Makuladegeneration (Englische Version);
摘要： Choroidal neovascularizations (CNV) occur not only in age-related macular degeneration (AMD), but also in numerous other macular and retinal disorders of varying etiology and, if left untreated, can cause irreversible visual loss. The diagnosis of CNV as well as the indication for treatment should be made in the same way as in neovascular AMD: On initial diagnosis: best-corrected visual acuity, fundus examination, optical coherence tomography (OCT), and fluorescein angiography. At follow-up: best-correct visual acuity, fundus examination, OCT, and, depending on findings, fluorescein angiography. Active CNV should be treated with intravitreal operative medication (IVOM) using vascular endothelial growth factor (VEGF) inhibitors if patients have visual acuity of at least 0.05 or if there is sufficient reason to assume that visual acuity could increase to over 0.05 under treatment. Underlying disorders can include, e.g., high myopia, angioid streaks, central serous chorioretinopathy, active and inactive uveitis of varying etiology, including retinochoroiditis, chorioretinitis, and choroiditis, eye injuries, retinal dystrophies, e.g., best disease and pattern dystrophies, idiopathic CNV, subretinal masses (osteomas, hamartomas, nevi). If CNV is not present as a complication in the above-mentioned disorders, IVOM with VEGF inhibitors should not be performed. Ranibizumab and aflibercept are approved in Germany for the treatment of CNV secondary to pathologic myopia. Ranibizumab has been approved in Germany since 12/2016 for the treatment of CNV in disorders other than neovascular AMD and pathologic myopia irrespective of the underlying disease. The other VEGF inhibitors, aflibercept and bevacizumab, can be used off-label. Due to its overall significantly poorer treatment results, photodynamic therapy (PDT) should only be used in exceptional cases and extrafoveal localization. After one initial intravitreal administration of VEGF inhibitors, further CNV activity should be monitored monthly for the first 6 months (see point 2). In the case of persisting or recurrent activity, repeated IVOM should be performed. Depending on disease course, the follow-up interval might be extended 6 months after the last IVOM. In individual justified cases (e.g., patients requiring frequent re-injections), a different treatment regimen (e.g., treat and extend) can be considered in the further course. If visual acuity drops below 0.05 on anti-VEGF treatment, or no further positive treatment outcome is expected (e.g., in the presence of atrophy and/or fibrosis), treatment should be discontinued, unless there is a clear possibility that visual acuity could increase again to over 0.05 under treatment. If no improvement is seen under therapy with a certain VEGF inhibitor, or if deterioration occurs, one can consider switching to an alternative VEGF inhibitor.
关键词： Choroidal neovascularization,Myopia,Retinal dystrophies,Ranibizumab,VEGF inhibitors,Uveitis,Idiopathic CNV,Central serous chorioretinopathy,Angioid streaks,Photodynamic therapy,Subretinal tumors,Aflibercept,Bevacizumab,Eye injuries
更新于2025-09-19 17:15:36
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PDG31 COST-EFFECTIVENESS OF RANIBIZUMAB VERSUS LASER PHOTOCOAGULATION OR OBSERVATION FOR THE TREATMENT OF MACULAR EDEMA SECONDARY TO RETINAL VEIN OCCLUSION: FROM CHINESE SOCIETAL PERSPECTIVE
摘要： To evaluate the cost-effectiveness of ranibizumab compared with laser photocoagulation or no treatment (observation) in patients with macular edema secondary to branch retinal vein occlusion (BRVO-ME) and macular edema secondary to central retinal vein occlusion (CRVO-ME), respectively, from the Chinese societal perspective. Methods: A Markov model was constructed to simulate the long-term outcomes and costs of Chinese BRVO-ME and CRVO-ME patients. Model health states were de?ned by increments of 10 letters in best corrected visual acuity (BCVA) ranging from # 25 letters to 86-100 letters, with an extra absorbing state ’death’. Lifetime horizon was used, with a 1-month cycle length. Transition probabilities were calculated from the BLOSSOM clinical trial and CAMELLIA clinical trial. Health state utilities were estimated through literature, and costs were estimated from experts consultation of 6 hospitals in China and published literature. The primary outcomes of the model were costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). Uncertainty was addressed via univariate and probabilistic sensitivity analyses. Results: For BRVO-ME patients, lifetime costs of ranibizumab and laser photocoagulation were U80,834 and U44,799, respectively; lifetime QALYs gained were 8.95 and 8.31, respectively. Adopting a willingness to pay of U180,000/ QALY (3 times per-capita GDP, 2017 China) as the threshold, ranibizumab was found to be cost-effective compared with laser photocoagulation, with the ICER of U56,303/QALY. For CRVO-ME patients, lifetime costs of ranibizumab and observation were U120,246 and U117,757, respectively; lifetime QALYs gained were 9.48 and 8.93, respectively. Ranibizumab was found to be cost-effective compared with observation, with the ICER of U4,525/QALY. Univariate and probabilistic sensitivity analysis demonstrated the robustness of the results. Conclusions: From Chinese societal perspective, ranibizumab is the cost-effective therapy for both the treatment of BRVO-ME and CRVO-ME when compared to laser photocoagulation and observation, respectively.
关键词： ranibizumab,retinal vein occlusion,cost-effectiveness,macular edema,laser photocoagulation
更新于2025-09-16 10:30:52
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RATES AND RISK FACTORS FOR RECURRENCE OF RETINOPATHY OF PREMATURITY AFTER LASER OR INTRAVITREAL ANTI–VASCULAR ENDOTHELIAL GROWTH FACTOR MONOTHERAPY
摘要： To determine the rates and risk factors of recurrent retinopathy of prematurity (ROP) treated by laser photocoagulation, intravitreal bevacizumab (IVB) monotherapy, or intravitreal ranibizumab (IVR) monotherapy. In this retrospective cohort study, consecutive infants with Type 1 ROP who received laser, IVB, or IVR treatments were followed for at least 75 weeks of postmenstrual age. Data analysis was performed between March 2010 and February 2017 in Chang Gung Memorial Hospital, Linkou, Taiwan. A total of 176 infants (340 eyes) were included in this study. The mean follow-up was 197.3 ± 110 weeks. All of the baseline demographic and ROP characteristics among the laser, IVB, and IVR groups were similar. The overall recurrence rate after treatment was 44 of 340 eyes (12.9%). The IVB group had a recurrence rate of 10.0%, followed by the laser group (18.0%) and the IVR group (20.8%); however, these rates were not signi?cantly different (P = 0.0528). Compared with the laser group, the IVB and IVR groups exhibited recurrence at later ages (43.4 ± 3.5 weeks for the IVB group, 42.3 ± 2.0 weeks for the IVR group, and 39.5 ± 2.8 weeks for the laser group; P = 0.0058). The mean interval of recurrence from initial treatment in the laser group was 3.6 ± 1.4 weeks compared with 8.8 ± 3.9 weeks and 8.3 ± 1.6 weeks in the IVB and IVR groups, respectively (P = 0.0001). Overall, the independent risk factors of recurrence included an early postmenstrual age at initial treatment (P = 0.0160), Zone I (P = 0.0007), low Apgar score (P = 0.0297), and multiple births (P = 0.0285). There was no signi?cant difference in progression to retinal detachment among the three groups (laser: 3/61, 4.9%; IVB: 2/231, 0.9%;and IVR: 1/48, 2.1%; P = 0.2701). Laser, IVR, and IVB are effective for Type 1 ROP. Retinopathy of prematurity recurrence requiring re-treatment was encountered as late as 50 weeks of postmenstrual age after IVB or IVR but earlier after laser. Longer follow-up for infants treated with anti–vascular endothelial growth factor is needed, especially in patients with signi?cant risk factors such as an early postmenstrual age at initial treatment, Zone I ROP, low Apgar score, and multiple births.
关键词： ranibizumab,risk factors,bevacizumab,rates,laser,anti-VEGF,recurrent retinopathy of prematurity
更新于2025-09-12 10:27:22
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Efficacy and safety of ranibizumab with or without panretinal laser photocoagulation versus laser photocoagulation alone in proliferative diabetic retinopathy – the PRIDE study
摘要： Purpose: Panretinal photocoagulation (PRP) is the current standard of care in proliferative diabetic retinopathy (PDR). However, treatment with anti-vascular endothelial growth factor agents might offer better patient outcomes with fewer side-effects. The PRIDE study aimed to assess the efficacy and safety of ranibizumab with or without PRP compared with PRP alone in patients with PDR. Methods: A total of 106 PDR patients without diabetic macular oedema were randomized to receive ranibizumab 0.5 mg monotherapy (n = 35), PRP (n = 35) or combined ranibizumab 0.5 mg/PRP (n = 36). The primary objective of this 12-month, multicentre, phase II study was to investigate the change in area of retinal neovascularization (NV). Complete regression of leakage and best-corrected visual acuity (BCVA) were key secondary end-points. Results: At Month 12, there was a statistically significant difference of ?2.83 mm2 in the least square mean change in NV area between the ranibizumab monotherapy and PRP group, favouring ranibizumab (95% CI [?5.45; ?0.21], p = 0.0344). At Month 3, 67%/0%/67% of the patients in the ranibizumab/PRP/combination groups, respectively, showed complete regression of leakage from NVs, while at Month 12, 28%/8%/18% showed complete regression of leakage from NVs. BCVA change was greater in the ranibizumab group compared with the PRP monotherapy group at Month 12 (+1.6 letters; 95% CI [?2.3; 5.5] versus ?3.9 letters; 95% CI [?7.8; ?0.1], p = 0.0495). Conclusions: Ranibizumab monotherapy is an alternative treatment option to laser treatment in patients with PDR. Ranibizumab showed stronger effects on NV leakage and area reduction while offering better visual acuity results than PRP alone.
关键词： ranibizumab,proliferative diabetic retinopathy,retinal neovascularization,panretinal laser photocoagulation,PRIDE study,anti-VEGF therapy
更新于2025-09-12 10:27:22