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The effectiveness of EYLEA® (aflibercept) in treating retinal diseases is closely linked to EYLEA® pharmacokinetics that determine how the drug is absorbed, distributed, metabolized, and eliminated. 

This article provides a detailed explanation of the pharmacokinetics of EYLEA® and their clinical relevance in optimizing dosing strategies and patient outcomes.

Key Takeaways

  • EYLEA® is a recombinant fusion protein that inhibits VEGF-A, VEGF-B, and PlGF.
  • It is approved for wet age-related macular degeneration (AMD), macular edema due to retinal vein occlusion (RVO), diabetic macular edema (DME), diabetic retinopathy (DR), and retinopathy of prematurity (ROP).
  • The peak plasma levels occur within 1–3 days and become undetectable within two weeks
  • Due to its large molecular weight (~115 kDa), it remains confined to the vitreous and systemic plasma with minimal tissue penetration
  • EYLEA® undergoes target-mediated clearance by binding VEGF, followed by proteolytic degradation into peptides and amino acids. It is not metabolized by CYP450 enzymes.
  • The drug’s systemic half-life is ~5–6 days, while intraocular elimination is significantly slower.
  • EYLEA® injection dose starts with monthly injections, transitioning to extended intervals (every 8–12 weeks) based on disease response.
  • EYLEA® vials must be refrigerated at 2–8°C (36–46°F), protected from light, and not frozen to maintain efficacy.

What Is EYLEA®?

EYLEA® is the brand name for aflibercept, a recombinant fusion protein that inhibits vascular endothelial growth factor (VEGF-A, VEGF-B) and placental growth factor (PlGF) involved in pathological angiogenesis and vascular permeability. 

It acts as a soluble decoy receptor to bind VEGF with high affinity and prevent its interaction with native VEGF receptors on endothelial cells. 

The inhibition reduces abnormal neovascularization and decreases vascular leakage in retinal diseases where there is excessive VEGF activity. [1]

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EYLEA®’s approved indications include: 

  • Neovascular (wet) age-related macular degeneration (AMD) — It inhibits VEGF-driven choroidal neovascularization and reduces macular edema and vision loss.
  • Macular edema following retinal vein occlusion (RVO) — It reduces vascular permeability and macular swelling in both central (CRVO) and branch (BRVO) retinal vein occlusion.
  • Diabetic macular edema (DME) and diabetic retinopathy (DR) — It controls diabetic retinal microvascular complications by inhibiting VEGF-induced leakage and neovascularization.
  • Retinopathy of prematurity (ROP) — It is also used in premature infants to treat VEGF-mediated retinal neovascularization.

EYLEA® Pharmacokinetics

Given that EYLEA® is administered intravitreally, its systemic pharmacokinetics differ significantly from conventional drug administration. Below is a detailed breakdown of each stage.

Absorption 

EYLEA® is not administered systemically, but rather intravitreally. This means absorption into the systemic circulation is limited. However, some degree of systemic exposure does occur. 

After a 2 mg intravitreal injection per eye, the mean peak plasma concentration (Cmax) of free aflibercept varies by condition: [2]

  • Wet AMD — 0.02 mcg/mL (range: 0–0.054 mcg/mL)
  • RVO — 0.05 mcg/mL (range: 0–0.081 mcg/mL)
  • DME — 0.03 mcg/mL (range: 0–0.076 mcg/mL)

The peak systemic concentrations occur within 1–3 days post-injection and the plasma levels of free aflibercept become undetectable within two weeks post-injection. [3]

When administered every four weeks, aflibercept does not accumulate in the plasma because the systemic clearance keeps pace with repeated intravitreal dosing.

The estimated maximum plasma concentration of free aflibercept is more than 100-fold lower than the concentration required for significant systemic VEGF inhibition. [4]

Distribution

Since aflibercept is a large recombinant fusion protein, its distribution is primarily confined to extracellular spaces. 

Following intravenous administration, the estimated volume of distribution for free aflibercept is ~6L. 

Aflibercept does not extensively penetrate tissues outside the eye because of its high molecular size (~115 kDa). [5] It remains largely confined to the vitreous and systemic plasma, with minimal extravasation into interstitial compartments.

The drug’s ocular half-life is significantly longer than its systemic half-life, which allows for sustained VEGF suppression over several weeks. 

In a rabbit model study, the estimated half-lives of aflibercept were 94.1 hours in the vitreous, 48.0 hours in the aqueous humor, and 58.2 hours in the retina/choroid. [6]

Metabolism 

Aflibercept does not undergo hepatic metabolism like small-molecule drugs. Instead, it is eliminated through two primary mechanisms: 

  1. Target-mediated clearance
  2. Proteolysis

Target-mediated clearance occurs as aflibercept binds to endogenous VEGF and forms a complex that is subsequently internalized and degraded. This process is saturable, meaning that as VEGF levels increase, aflibercept clearance also increases due to higher levels of target binding. 

Any unbound aflibercept undergoes proteolytic degradation into small peptides and amino acids, which are recycled or eliminated from the body. 

No cytochrome P450 enzyme metabolism is involved so drug interactions via hepatic metabolism are unlikely.

Elimination

The elimination of free aflibercept from systemic circulation follows a first-order kinetic process, with a plasma half-life of approximately 5–6 days when administered intravenously. 

Since aflibercept is a large protein, renal elimination is not a significant pathway and clearance occurs mainly through reticuloendothelial and proteolytic mechanisms. 

In contrast, the elimination from the vitreous is significantly slower, allowing for sustained VEGF inhibition over several weeks. The prolonged ocular half-life is the basis for EYLEA®’s dosing schedule, as the drug continues to exert its effect long after systemic clearance has occurred. 

EYLEA® injection dose in adults varies by condition. The recommended dosage for its indicated conditions includes: 

  • Wet AMD — 2 mg (0.05 mL) once every four weeks (monthly) for the first 12 weeks (three months), then every eight weeks (two months) 
  • Macular edema following RVO — 2 mg (0.05 mL) every four weeks (monthly)
  • DME and DR — 2 mg (0.05 mL) every four weeks for the first five injections (20 weeks, five months), then every eight weeks (two months) [7]

The safety and efficacy of EYLEA® for AMD, RVO, DME, and DR are not established in children.

For ROP, 0.4 mg (0.01 mL) of EYLEA® per eligible eye is administered as a single injection, with a minimum ten-day interval before retreatment. Bilateral injections can be given on the same day.

How Is EYLEA® Administered?

EYLEA® is administered via intravitreal injection using a strict aseptic technique to prevent infections and complications. Here are the steps to administer it: [4]

  1. Confirm the patient’s identity, diagnosis, and prescribed dosage, and check the EYLEA® vial for the expiration date, damage, or contamination.
  2. Ensure all necessary sterile equipment is ready, including gloves, drapes, an eyelid speculum, a 30-gauge x ½-inch injection needle, and a filter needle (to withdraw the drug from the vial).
  3. Use a filter needle to draw 0.05 mL (adults) or 0.01 mL (ROP) of EYLEA® injection dose from the vial into a sterile syringe.
  4. Remove the filter needle and attach a 30-gauge x ½-inch injection needle.
  5. Apply topical anesthetic drops and 5% povidone-iodine solution to the conjunctival sac.
  6. Identify the injection site in the vitreous cavity, approximately 3.5–4 mm posterior to the limbus (pars plana region). Avoid the central macula.
  7. Using a 30-gauge x ½-inch needle, insert the needle perpendicular to the sclera and inject 0.05 mL (adults) or 0.01 mL (ROP) slowly into the vitreous humor.
  8. Discard the used vial, syringe, filter needle, and injection needle as per biohazard disposal protocols.
  9. If treating the contralateral eye, repeat the entire procedure using a new sterile setup.

Does EYLEA® Have Any Adverse Effects?

EYLEA® does have a few side effects, however, there’s no significant risk of drug toxicity. In a side-by-side comparison using ARPE-19 cells, both aflibercept and the anti-VEGF agent ranibizumab demonstrated no toxicity, even at the highest tested concentration of 1 mg/mL. [8]

The most common adverse reactions (≥5%) reported in patients receiving EYLEA® are: 

  • Conjunctival hemorrhage
  • Eye pain
  • Cataract
  • Vitreous detachment
  • Vitreous floaters
  • Increased intraocular pressure

FAQs

What Is the Half-Life of EYLEA®?

The systemic half-life of EYLEA® is ~5–6 days, while the ocular half-life was studied to be around ~94.1 hours in the vitreous humor. 

How to Store EYLEA®?

EYLEA® should be stored refrigerated at 2°C–8°C (36°F–46°F) and must not be frozen. It should remain in its original carton to protect it from light exposure and should not be used past the expiration date printed on the packaging.

When Is EYLEA® Contraindicated?

EYLEA® is contraindicated in ocular or periocular infection, active intraocular inflammation, and hypersensitivity. 

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Final Words

EYLEA® should only be sourced from licensed pharmaceutical distributors or authorized specialty pharmacies. Purchasing directly from the manufacturer or verified wholesalers guarantees product integrity and minimizes the risk of counterfeit medications. 

For a trusted and secure purchasing experience, order EYLEA® from Medica Depot, a reliable supplier since 2007. We ensure safe procurement for your patients, provide product authenticity assurance, and offer a 100% money-back guarantee. Contact the sales team at Medica Depot to buy EYLEA® at wholesale prices today. 

References: 

  1. Yang LPH, McKeage K. Intravitreal Aflibercept (EYLEA®): A Review of Its Use in Patients with Macular Oedema Secondary to Central Retinal Vein Occlusion. Drugs & Aging. 2014;31(5):395-404. doi:https://doi.org/10.1007/s40266-014-0176-2
  2. Haymarket. EYLEA® Dosage & Rx Info | Uses, Side Effects. MPR. Published 2024. Accessed February 15, 2025. https://www.empr.com/drug/EYLEA®/
  3. EYLEA®. Medscape.com. Published February 12, 2025. Accessed February 15, 2025. https://reference.medscape.com/drug/EYLEA®-EYLEA®-hd-aflibercept-intravitreal-999705
  4. HIGHLIGHTS of PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.pdf
  5. Adams BS, Sorhaitz W, Stringham J. Aflibercept. PubMed. Published 2022. https://www.ncbi.nlm.nih.gov/books/NBK582136/
  6. Park SJ, Choi Y, Na YM, et al. Intraocular Pharmacokinetics of Intravitreal Aflibercept (EYLEA®) in a Rabbit Model. Investigative Opthalmology & Visual Science. 2016;57(6):2612. doi:https://doi.org/10.1167/iovs.16-19204
  7. EYLEA® Dosage Guide. Drugs.com. Published 2024. Accessed February 15, 2025. https://www.drugs.com/dosage/EYLEA®.html
  8. Ammar DA, Mandava N, Kahook MY. The effects of aflibercept on the viability and metabolism of ocular cells in vitro. Retina (Philadelphia, Pa). 2013;33(5):1056-1061. doi:https://doi.org/10.1097/IAE.0b013e31827b646d

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