Retina Society 2024: Population pharmacokinetic modeling and simulation of ocular clearance of aflibercept 8 mg and 2 mg

Video Transcript

Editor's note - This transcript has been edited for clarity.

David Hutton:

Hi. I'm David Hutton of Ophthalmology Times. The Retina Society recently held its annual meeting in Lisbon, Portugal. At that meeting, Dr. Diana Do made a presentation titled Population Pharmacokinetic Modeling and Simulation of Ocular Clearance of aflibercept 8 mg and 2 mg and Association with Durability of Effect. Dr. Do, thank you so much for joining me today. First, tell me about the key points of your presentation.

Diana Do, MD:

Thank you, David. Well, we conducted very impactful research, because we wanted to evaluate the pharmacokinetic and patient specific characteristics that might affect dosing interval duration for aflibercept 8 milligrams. And this is important because the FDA approved aflibercept 8 milligrams for both neovascular age related macular degeneration and diabetic macular edema. To do this research, we conducted a population pharmacokinetic model that was developed using data from more than 2700 patients across 16 clinical trials, and we evaluated their serum plasma concentrations of aflibercept. We also assess through different models, different patient characteristics that might affect dosing interval shortening or dosing interval extension. And our results were very interesting. We actually showed that between aflibercept 8 milligrams and aflibercept 2 milligrams, the ocular clearance was different between the two drugs. In fact, the population pharmacokinetic modeling estimated the ocular clearance was 34% slower for aflibercept 8 milligram drug product compared to aflibercept 2 milligram drug product. In addition, when we looked at the median free aflibercept ocular concentration, it was estimated to remain above the reference concentrations for 6 to nearly 9 weeks longer for the afibercept 8 milligram dose compared to the 2 milligram dose. And finally, in our modeling, we estimate about 50% of patients are estimated to maintain aflibercept ocular concentrations above 9 times that necessary for the dissociation constant of binding to VEGF inside the eye for up to 20 weeks. So, this data is very important because it gives clinicians more information about why some patients might need more frequent dosing, while others might have more extended durability between aflibercept concentrations.

Furthermore, our studies also showed that the rate of ocular clearance and baseline retinal thickness also contributes to interval shortening or dosing. For example, a patient who has slower ocular clearance of aflibercept 8 milligrams and starts off with lower levels of retinal thickening, they're more likely to have sustained durability between injections, and therefore need fewer injections between their whole disease management. Conversely, if a patient has faster ocular clearance and has more severe and edematous retina at baseline, they be maybe more likely to require interval shortening at some period during their disease management.

David Hutton:

Are there any specific patient characteristics or clinical conditions that might influence these results?

Diana Do, MD:

Well, a lot of these diseases, for both diabetic eye disease and neovascular AMD, there are a lot of variables that can affect the patient's interval dosing. In our study, we found that baseline retinal thickness, if you're in the highest tertile retinal thickness of 490 microns or greater, those eyes were more likely to require interval shortening at some time point. But we also saw in the data from the Phase 3 clinical trials that over time, if you initially needed interval shortening, sometimes in the second year, actually, once the disease was under control, many of those patients were able to be extended significantly during the second year of treatment.

David Hutton:

And lastly, what is the next step for this research?

Diana Do, MD:

Aflibercept 8 milligrams has now been in use since its FDA approval. We're waiting for the 3-year follow up data from both the PULSAR and the PHOTON clinical trials, and that would be exciting, because it will reveal to us what happens long-term in these patients, and how 4 times the dose of aflibercept, which is available in the 8 milligram dose … how that impacts the disease management over time.