Intraocular Pharmacokinetics of Aflibercept and Vascular Endothelial Growth Factor-A

Celik, Nil; Scheuerle, Alexander F.; Auffarth, Gerd U.; Kopitz, Jürgen; Dithmar, Stefan

doi:10.1167/iovs.15-16418

Cited by 18 publications

(15 citation statements)

References 20 publications

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“…After subsequent absorption of drug into the systemic circulation a portion of the administered drug binds with endogenous VEGF in the eye, forming inactive aflibercept VEGF complex (Unbound to VEGF) and are present in a stable inactive form. 15 The mean c-max of free aflibercept in the plasma was 0.05 mcg/ml and was attained in 1-3 days. Aflibercept is a therapeutic protein undergoes elimination through both target mediated disposition via binding to free endogenous VEGF and metabolism via proteolysis.…”

Section: Pharmokineticsmentioning

confidence: 91%

Aflibercept for diabetic macular edema: a concise review

Haridoss

Sundaram

George

et al. 2017

Int J Basic Clin Pharmacol

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Diabetic retinopathy and diabetic macular edema are associated with loss of vision in patients with diabetes worldwide. The treatment requires a multidisciplinary interventional approach. Among the available management options for DME, laser photocoagulation has been the standard of care. Due to its slow progression and inability to reverse the vision loss, an alternative treatment is needed. The role of vascular endothelial growth factors (VEGF) and inflammatory mediators led to the development of anti-VEGF agents, that stimulates retinal vasculogenesis and angiogenesis. Intravitreal aflibercept is an anti-angiogenic soluble decoy receptor with trap technology employed by fusion of multiple endogeneous receptor component, approved for the treatment of DME. Clinical trials of aflibercept comparing it with laser photocoagulation and other anti-VEGF have shown reliable efficacy, providing significantly positive visual and anatomical results. However, treatment regimens with monthly clinical visits and injections, challenge the patients comfort, thereby requiring the need to identify better strategies to lower injection frequencies.

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Section: Pharmokineticsmentioning

confidence: 91%

Aflibercept for diabetic macular edema: a concise review

Haridoss

Sundaram

George

et al. 2017

Int J Basic Clin Pharmacol

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“…ELISA analytical kits for bevacizumab (kit #AVA-E-U51) and ranibizumab (kit #LUC-E-U52) were obtained from United Immunoassay Inc., San Bruno, CA USA. Aflibercept was analyzed using an ELISA procedure as described Celik et al ( 20 )…”

Section: Methodsmentioning

confidence: 99%

“…Bevacizumab and ranibizumab ELISA assays were performed as per manufacturer’s instructions except for a substitution of the base analytical standard diluent material which was taken from the pharmaceutical preparations obtained and diluted as described below. Aflibercept ELISA was performed as described by Celik et al ( 20 ), except for a substitution of the base analytical standard diluent material which was taken from the pharmaceutical preparations obtained and diluted as described below. Drug standard dilutions were diluted with the manufacturer’s diluent solution (or as described by Celik for aflibercept), PBS, as well as with the new formula, as described below.…”

Section: Methodsmentioning

confidence: 99%

Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions

et al. 2018

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PurposeStudies were conducted to investigate dilute solutions of the monoclonal antibody (mAb) bevacizumab, mAb fragment ranibizumab and fusion protein aflibercept, develop common procedures for formulation of low concentration mAbs and identify a stabilizing formulation for anti-VEGF mAbs for use in in vitro permeation studies.MethodsExcipient substitutions were screened. The most stabilizing formulation was chosen. Standard dilutions of bevacizumab, ranibizumab and aflibercept were prepared in PBS, manufacturer’s formulation, and the new formulation. Analysis was by SE-HPLC and ELISA. Stability, disaggregation and pre-exposure tests were studied.ResultsWhen Avastin, Lucentis and Eylea are diluted in PBS or manufacturer’s formulation, there is a 40–50% loss of monomer concentration and drug activity. A formulation containing 0.3% NaCl, 7.5% trehalose, 10 mM arginine and 0.04% Tween 80 at a pH of 6.78 stabilized the mAbs and minimized the drug loss. The formulation also disaggregates mAb aggregation while preserving the activity. Degassing the formulation increases recovery.ConclusionsWe developed a novel formulation that significantly stabilizes mAbs under unfavorable conditions such as low concentration or body temperature. The formulation allows for tissue permeation experimentation. The formulation also exhibits a disaggregating effect on mAbs, which can be applied to the manufacture/packaging of mAbs and bioassay reagents.Electronic supplementary materialThe online version of this article (10.1007/s11095-018-2368-7) contains supplementary material, which is available to authorized users.

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“…In humans, the half-life of aflibercept increased with an increase in dose after intravenous administration of aflibercept, ranging from 1.7 days (0.3 mg/kg cohort) to 7.4 days (5.0 mg/kg cohort) [ 158 ]. However, no human pharmacokinetic data of aflibercept is available after intravitreal administration [ 159 ]. An aflibercept (2.0 mg, 50 μL) half-life of 1.5 and 2.2 days was found in the aqueous humor of vitrectomized and non-vitrectomized macaque eyes respectively [ 160 ].…”

Section: Potential Strategies To Overcome Challenges In Antibody-bmentioning

confidence: 99%

Overview of Antibody Drug Delivery

2018

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Monoclonal antibodies (mAbs) are one of the most important classes of therapeutic proteins, which are used to treat a wide number of diseases (e.g., oncology, inflammation and autoimmune diseases). Monoclonal antibody technologies are continuing to evolve to develop medicines with increasingly improved safety profiles, with the identification of new drug targets being one key barrier for new antibody development. There are many opportunities for developing antibody formulations for better patient compliance, cost savings and lifecycle management, e.g., subcutaneous formulations. However, mAb-based medicines also have limitations that impact their clinical use; the most prominent challenges are their short pharmacokinetic properties and stability issues during manufacturing, transport and storage that can lead to aggregation and protein denaturation. The development of long acting protein formulations must maintain protein stability and be able to deliver a large enough dose over a prolonged period. Many strategies are being pursued to improve the formulation and dosage forms of antibodies to improve efficacy and to increase the range of applications for the clinical use of mAbs.

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Intraocular Pharmacokinetics of Aflibercept and Vascular Endothelial Growth Factor-A

Cited by 18 publications

References 20 publications

Aflibercept for diabetic macular edema: a concise review

Aflibercept for diabetic macular edema: a concise review

Formulation Stabilization and Disaggregation of Bevacizumab, Ranibizumab and Aflibercept in Dilute Solutions

Overview of Antibody Drug Delivery

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