Michael Stewart, MD, Professor and Chairman Emeritus of Ophthalmology at the Mayo Clinic in Jacksonville, Florida, talks with Ophthalmology 360 about his study presented at the 2024 AAO Annual Meeting, titled “PopPK Modeling and Simulation of Ocular Clearance for Aflibercept 8mg vs. 2mg and Associated Durability of Effect.”
Michael Stewart, MD:
I’m here at the American Academy of Ophthalmology Annual Meeting 2024 and I’m shortly going to be giving a poster presentation entitled Population Pharmacokinetic Modeling of Aflibercept 8 mg Compared to Aflibercept 2 mg. As a matter of disclosure, I am a consultant for both Regeneron as well as Bayer Pharmaceuticals.
The aflibercept 8 mg is a new drug that has just been introduced to the American market approximately 1 year ago. It differs from the 2 mg drug, not only in terms of its quadruple dose, but also in terms of the excipients and the pH of the solution in which it’s packaged. It’s not a new molecule, but rather it’s a new drug. The aflibercept 8 mg was evaluated in the phase 3 PULSAR study for age-related macular degeneration and the PHOTON study for diabetic macular edema. It was found to be non-inferior compared to aflibercept 2 mg as given per label.
My colleagues and I decided to try to investigate why the variability signals that were seen in the PULSAR and PHOTON trials, meaning that many of the patients receiving 8 mg were extended to q12 weeks or q16 weeks and in the second year, as long as q24 weeks. Why did those safety signals exist? Is there a pharmacokinetic rationale that helps explain this? What we did was we developed a pharmacokinetic model that has the various inputs, both subcutaneous, intravenous and intraocular, and then the drugs then move into the plasma space from there into 2 secondary spaces. Then the drug ultimately is removed from the body by both binding within platelets, irreversible binding to VEGF, as well as removal via various biochemical mechanisms within the body. We took samples from 2,744 patients over the course of 16 trials who had received subcutaneous intravenous or intravitreal aflibercept, and then had their plasma samples drawn and the aflibercept bound and unbound concentrations measured in the plasma.
We had just over 15,000 measurements of bound aflibercept in the plasma to VEGF as well as unbound. From that, we used non-mechanistic model to model exactly what the clearance was of aflibercept 8 mg as well as 2 mg from the eye subsequently into the plasma space and then removal from the body. We found that the rate limiting step here was actually removal of aflibercept from the eye into the plasma. And for that reason we could then use that the plasma concentrations to reverse model and determine the clearance from the vitreous. What we found several different important features. One is that the clearance of aflibercept 8 mg from the eye is 34% slower than that we see from the 2 mg. We found that the average extended durability of 8 mg based on the modeling over that we see in 2 mg is between 6 and 8.9 weeks. We found that if we use the nine times factor of aflibercept concentration over the PKD, we also found that about 49% of patients receiving 8 mg of aflibercept still met that threshold 20 weeks after the injection of aflibercept within the eye.
Secondly, we looked at factors that we thought might have influenced patients’ need for either shortening of their interval from longer between 12 or 16 week intervals, as well as the ability to extend them in year 2 of the trials. We found a couple of things. One was the area under the curve. That is the overall average concentration of aflibercept in the eye as measured by our model. When we looked at the terciles of the patient’s response, we found that those with the highest area under the curve had the least frequent need for decreasing their treatment interval over the course of 1 and 2 years.
The second thing we looked at was the central retinal thickness at baseline. From that we determined that those eyes with greater central retinal thickness had the inability to actually be extended during the second year. CRT and area under the curve seemed to be predictive factors for patients in terms of decreasing the interval during the first year and extending it within the second year. Overall, the take-home message here is that aflibercept 8 mg seems to be a different drug than aflibercept 2 mg and not just because of the concentration. We determined that because of that 34% slower clearance out of the eye of the 8 mg versus the 2 mg. The result of that is the extended durability anywhere from 6 to 8.9 weeks over that of the 2 mg and an impressive 49% of patients who are above the 9 times concentration of the KD.
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