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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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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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Retinal vascular changes and aqueous humor cytokines changes after aflibercept intravitreal injection in treatment-na?ve myopic choroidal neovascularization
摘要： The aim of the study was to assess retinal vascular changes using optical coherence tomography angiography (OCTA) and aqueous humour changes of vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) levels in treatment-na?ve myopic choroidal neovascularization (mCNV) after aflibercept intravitreal injection. To explore the correlation between clinical and laboratory parameters. Fifteen eyes of 15 patients with treatment-na?ve mCNV underwent 2 intravitreal injections of aflibercept. Main outcome measures were best corrected visual acuity (BCVA), central retinal thickness (CRT) and external limiting membrane (ELM) visualization at OCT, lesion area and leakage at fluorescein angiography (FA), OCTA flow area and selected area at baseline and after the injections. Analysis of VEGF and PlGF in the aqueous humor was performed before each injection in cases and prior to cataract surgery on 10 patients as included as controls. Median BCVA increased from 0.6 to 0.3 logMAR (p < 0.001); CRT decreased from 387.5 to 267 micron (p < 0.001); FA area from 0.8 to 0.5 mm2 and OCTA area from 0.9 to 0.5 mm2 (p = 0.005). PIGF values changed from 1.8 to 1.4 pg/ml (p = 0.019) and VEGF values from 3.4 to 0.5 pg/ml (p = 0.008). A significant correlation was found after treatment between PIGF levels and BCVA (rho = 0.006) and VEGF levels and BCVA (rho = 0.018); between PlGF and CRT (rho = 0.020), PlGF and ELM visualization (rho = 0.002) and PlGF and FA leakage (rho < 0.001). Our results showed a significant reduction of mCNV area after aflibercept in both FA and OCTA measurements; an improvement of BCVA, and a reduction of VEGF and PIGF levels related to inactivity of the disease.
关键词： retinal vascular changes,OCTA,PlGF,myopic choroidal neovascularization,intravitreal injection,aflibercept,VEGF,aqueous humor cytokines
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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Laser and Anti–Vascular Endothelial Growth Factor Agent Treatments for Retinal Arterial Macroaneurysm
摘要： Purpose: to describe the efficacy of laser and intravitreal injection of anti?vascular endothelial growth factor (anti-VEGF) agents for patients with symptomatic retinal arterial macroaneurysm (RAM). Design: From 2009 to 2016, we collected patients with exudative or hemorrhagic RAM all treated by focal laser photocoagulation. Methods: Nd:YAG laser was performed in patients with subinternal limiting membrane (sub-ILM) hemorrhage. Intravitreal anti-VEGF agents were given in eyes with macular exudation as adjuncts. Changes of visual acuity and central foveal thickness before and after treatment were recorded and compared with Wilcoxon signed-rank test. Results: Thirty-five eyes that underwent a single session of laser photocoagulation for RAM resulted in macroaneurysm regression. The hemorrhagic group included 24 eyes having ruptured macroaneurysms without macular exudation. Five eyes with simultaneous sub-ILM hemorrhage receiving Nd:YAG laser membranotomy had resolution of preretinal hemorrhage. Exudative RAM having cystoid macular edema or submacular fluid with or without ruptured macroaneurysms was treated by focal laser photocoagulation alone in 3, or combined with single intravitreal anti-VEGF agent in 8 eyes. All patients had significantly improved vision when comparing visual acuity at baseline and final follow-up (P = 0.00016). Significant reduction of macular thickness was also observed after laser monotherapy or combined treatment in exudative RAM (P = 0.018). Conclusions: Focal laser photocoagulation was helpful for the management of ruptured or leaky RAM. Combined focal laser and intravitreal anti-VEGF agents could better reduce macular exudation caused by RAM. Additionally, Nd:YAG laser was a safe and effective method to remove the sub-ILM hemorrhage caused by RAM.
关键词： retinal arterial macroaneurysm,argon laser,bevacizumab,aflibercept
更新于2025-09-11 14:15:04
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Foveal structure during the induction phase of anti-vascular endothelial growth factor therapy for occult choroidal neovascularization in age-related macular degeneration
摘要： Purpose: To evaluate the efficacy of monthly injections of aflibercept and ranibizumab on foveal structure after three months, for the treatment of occult choroidal neovascularization (CNV) in age-related macular degeneration (AMD). Methods: We retrospectively studied 103 eyes with treatment-na?ve neovascular AMD with occult and no classic CNV. Seventy-four of 103 eyes were treated with ranibizumab (intravitreal ranibizumab injection [IVR] group); 29 eyes were treated with aflibercept (intravitreal aflibercept injection [IAI] group). The best-corrected visual acuity and the retinal and choroidal structure at the fovea were evaluated using optical coherence tomography. Results: The total foveal thickness, the height of serous retinal detachments, and subfoveal choroidal thickness were compared with baseline, and the incidence of retinal pigment epithelial elevation significantly decreased in the IAI group compared with the IVR group. In contrast, the thickness of the sensory retina at the fovea significantly decreased in the IVR group when compared with the IAI group. The logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity improved more significantly in the IVR group (?0.085±0.164) than in the IAI group (?0.020±0.125) at 3 months (P=0.017). Conclusion: After intravitreal injection, aflibercept more rapidly reduced subretinal fluid and subfoveal choroidal thickness. In contrast, ranibizumab decreased the sensory retinal thickness compared with aflibercept. The responses of the retinal and choroidal tissue to these anti-VEGF agents may be different during the induction phase for eyes with occult CNV secondary to neovascular AMD.
关键词： occult,neovascular age-related macular degeneration,outer nuclear layer,aflibercept,retinal thickness,ranibizumab
更新于2025-09-10 09:29:36
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Aflibercept Treatment for Neovascular Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy Refractory to Anti-vascular Endothelial Growth Factor
摘要： Purpose: To report the results of switching treatment to vascular endothelial growth factor (VEGF) Trap-Eye (aflibercept) in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) refractory to anti-VEGF (ranibizumab and bevacizumab). Methods: This is a retrospective study involving 32 eyes from 29 patients; 18 were cases of neovascular AMD and 14 were cases of PCV. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) of spectral-domain optical coherence tomography were evaluated. Results: BCVA and CMT improved from 0.58 to 0.55 (p = 0.005) and from 404 to 321 μm (p < 0.001), respectively, after switching to aflibercept. The 14 eyes that received 6 or more aflibercept injections remained stable at 0.81 to 0.81 and 321 to 327 μm (p = 1.0, 0.29), respectively, after 3 aflibercept injections. The 10 eyes that received 3 or more bevacizumab injections after 3 or more aflibercept injections worsened, from 0.44 to 0.47 and from 332 to 346 μm (p = 0.06, 0.05), respectively. The results showed similar improvement of BCVA and CMT in neovascular AMD and PCV. Conclusions: Aflibercept seems to be effective for improvement and maintenance of BCVA and CMT for neovascular AMD and PCV refractory to anti-VEGF. Switching from aflibercept back to bevacizumab treatment may not be a proper strategy.
关键词： Aflibercept,Polypoidal choroidal vasculopathy,Bevacizumab,Macular degeneration,Anti-vascular endothelial growth factor
更新于2025-09-10 09:29:36
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The effect of ranibizumab and aflibercept treatment on the prevalence of outer retinal tubulation and its influence on retreatment in neovascular age-related macular degeneration
摘要： Background: We aimed to analyze the differences in the prevalence of outer retinal tubulation (ORT) in neovascular age-related macular degeneration (AMD) treated with anti-vascular endothelial growth factor (anti-VEGF) agents, either aflibercept or ranibizumab. Our further aim was to examine the changes in the frequency of injections of ranibizumab before and after ORT appearance. Methods: Two hundred thirty six eyes of 230 patients were included in the study (184 eyes treated with ranibizumab by pro re nata regimen (PRN), 52 eyes with aflibercept bimonthly) and followed for 6–24 months. Using optical coherence tomography (OCT), the first appearance of ORT was documented, and fixed time point evaluations were also made every six months to determine the existence of ORT. The number of injections, the presence or absence of subretinal hyperreflective material (SHRM) at treatment initiation and visual acuity were also noted. Results: The survival analysis with Cox proportional hazard model showed no significant difference between the ranibizumab and aflibercept groups in relation to the development of ORT (p = 0.79, hazard ratio 0.92). In the PRN treated ranibizumab group the number of injections showed significant decrease after ORT development (p = 0.004). When SHRM was present at treatment initiation the chance of developing ORT was 2.75 and 11.14 times higher in the ranibizumab and aflibercept groups, respectively. Conclusions: The prevalence of ORT increased over time independently from the chosen anti-VEGF drug. Our results suggest that upon the appearance of ORT a decrease in retreatments can be expected.
关键词： Prevalence,Anti-VEGF,Outer retinal tubulation,Subretinal hyperreflective material,Aflibercept,Retreatment
更新于2025-09-10 09:29:36
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Initial Utilization of Aflibercept in Exudative Age-related Macular Degeneration
摘要： Purpose: Intravitreal aflibercept, a fusion protein with high affinity for vascular endothelial growth factor, offers an alternative treatment for exudative age-related macular degeneration. Preclinical studies and early and late phase clinical trials suggest that aflibercept’s high binding affinity may impart greater durability of activity and increased efficacy compared to ranibizumab or bevacizumab. Methods: A total of 266 eyes of 249 patients with exudative age-related macular degeneration who received aflibercept after treatment with bevacizumab and/or ranibizumab were included in a retrospective review. Mean central subfoveal thickness on spectral-domain optical coherence tomography and mean logarithm of the minimal angle of resolution (logMAR) visual acuity were calculated at 1, 3, 6, and 12 months after the first aflibercept injection. Subgroup analyses were performed in eyes receiving at least 5 bevacizumab and/or ranibizumab injections in the 6 months prior to aflibercept and in eyes receiving at least 10 injections in the 12 months prior to aflibercept. Results: Eyes received an average of 14.7 (range 1-43) ranibizumab and/or bevacizumab treatments prior to initiation of aflibercept therapy. The mean central subfoveal thickness decreased from 300 to 275 μm at 1 month (p<0.001) and was maintained at 6 months. Mean logMAR visual acuity improved from 0.60 (Snellen equivalent 20/80) to 0.54 (20/70, p = 0.01) at 1 month and was stable at 0.55 at 6 months (Snellen equivalent 20/70, p = 0.11, n = 251). In 82 eyes receiving at least 5 injections in the 6 months prior to aflibercept treatment (average of 18.1 injections total), the central subfoveal thickness improved from 296 to 279 μm at 1 month (p<0.0001) and was maintained at 6 months (p<0.0001). Visual acuity did not change (0.48 [20/61] at 1 month compared to baseline, 0.49 [20/62], p = 0.634, and at 6 months 0.51 [20/65], p = 0.601). In 50 eyes receiving at least 10 injections in the 12 months prior to aflibercept treatment (average of 21.8 injections total), the mean central subfoveal thickness decreased by 17 μm at 1 month (p = 0.0007) and was maintained at 6 months (p = 0.013). Again, visual acuity did not change (0.46 [20/56] at 1 month, baseline 0.44 [20/56], p = 0.547, and 0.50 [20/63] at 6 months, p = 0.2445). Conclusions: Aflibercept is a valuable treatment alternative in patients previously treated with bevacizumab and/or ranibizumab injections. Stability of visual acuity and anatomic improvement on spectral-domain optical coherence tomography were observed after initiation of aflibercept treatment in those previously treated with ranibizumab and/or bevacizumab injections every 4-6 weeks.
关键词： Ranibizumab,Age-related macular degeneration,Choroidal neovascularization,Aflibercept,Bevacizumab
更新于2025-09-10 09:29:36
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Efficacy of intravitreal aflibercept monotherapy in retinopathy of prematurity evaluated by periodic fluorescence angiography and optical coherence tomography
摘要： Purpose To evaluate the efficacy of intravitreal aflibercept (IVA) in vascular and macular maturation in neonates with type 1 retinopathy of prematurity (ROP) and aggressive posterior retinopathy of prematurity (APROP). Materials and methods Thirty-six eyes of 18 patients with type 1 ROP or APROP in zone I or posterior zone II were enrolled in our study. At baseline, only fluorescein angiography (FA) was performed. After IVA injection, both FA and optical coherence tomography (OCT) were performed after 6.8 ± 0.8 (range 6–8) and 19 ± 0.9 (range 18–20) weeks to follow vascular and macular changes. Results Both diffuse flat neovascularization with leakage and abnormal vascular branching at the small arteriolar level were detected in all eyes (100%) at baseline FA. Regression of the disease was observed in 34 eyes (94.4%) in the first week with binocular indirect ophthalmoscopy. Early unresponsiveness in remaining two eyes of an infant required an IVA re-treatment. Late reactivation was detected only in 19.4% of eyes, none of which required treatment during 12 months of follow-up. The most common feature after IVA injection was abnormal branching at capillary level, which was noted in 100% in the first post-injection FA and 50.0% of all eyes in the second FA. Meanwhile, the end limit of vascularization was observed in zone III in 83.3% of eyes. No vascular abnormality was also detected in 27.3% of eyes. The OCT examination at a mean postmenstrual age of 43.4 weeks revealed cystoid macular changes in four eyes of two infants (11.1%), normal foveal contour in 30 eyes of 15 infants (83.3%) and matured ellipsoid zone at the foveal center in 28 eyes of 14 infants (77.8%). Macular maturation was complete in all eyes in the last OCT analyses. Conclusion Intravitreal aflibercept monotherapy has been an effective treatment in type I ROP and APROP with much lower early and late re-treatment rates because of early unresponsiveness and late reactivation, respectively. In most of the eyes, rapid vascular outgrowth beyond zone III together with normal macular maturation was observed more precisely by periodic FA and OCT.
关键词： Fluorescein angiography,Retinopathy of prematurity,Optical coherence tomography,Aflibercept
更新于2025-09-09 09:28:46