Population pharmacokinetic modeling and simulation of ocular clearance for aflibercept 8 mg and 2 mg and association with durability of effect

Abstract

Purpose : To evaluate ocular clearance (QE) and duration of effect for aflibercept 8 mg and 2 mg using population pharmacokinetic modeling and simulation (PopPK M&S) and compare model-estimated durability of effect to that observed in clinical trials.

Methods : A PopPK model was developed to characterize systemic and ocular disposition of aflibercept after intravitreal (IVT) administration. Aflibercept 8 mg and 2 mg IVT formulations are distinct, differing in molar concentration and excipients. The PopPK model was developed based on free and bound aflibercept concentrations in plasma from 2744 participants who received aflibercept by different routes of administration across 16 clinical trials, including CANDELA, PHOTON, and PULSAR. Ocular concentrations of free aflibercept were simulated over time for IVT aflibercept 8 mg and 2 mg for a combined population of 5000 DME and 5000 nAMD virtual patients using PopPK model-derived estimates of QE, and time above target ocular concentrations was determined. Target ocular concentrations were those required to bind vascular endothelial growth factor-A (VEGF-A) by 50%, 90%, and 99%, and model-estimated free aflibercept ocular concentration at the end of an 8-week dosing interval for aflibercept 2 mg (2q8).

Results : The PopPK model-estimated QE of free aflibercept was, unexpectedly, 34.4% lower for aflibercept 8 mg vs 2 mg (0.410 vs 0.625 mL/day), and the corresponding median time that concentrations remained above ocular targets was 6–8.9 weeks longer for aflibercept 8 mg. These results were consistent with observed durability in the PHOTON and PULSAR trials in which aflibercept 8 mg every 12 and 16 weeks (8q12 and 8q16) after 3 monthly doses demonstrated noninferior efficacy in mean best-corrected visual acuity to 2q8 at Week 48. Through Week 96, 47% and 53% of 8q16 patients in PHOTON and PULSAR, respectively, were able to extend their treatment interval to ≥20 weeks. Similarly, PopPK simulations estimated that 49.5% of patients maintain free aflibercept ocular concentrations above those required to bind VEGF-A by 90% for 20 weeks after aflibercept 8-mg dosing.

Conclusions : PopPK M&S estimated a 34.4% slower ocular clearance of free aflibercept and a 6- to 8.9-week longer duration of effect for aflibercept 8 mg vs 2 mg, consistent with the longer durability of effect observed for aflibercept 8 mg in clinical trials.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.