Integrated Population Pharmacokinetic Analysis of Intravitreal Aflibercept Drug Products

Neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) can cause substantial vision loss. The 2-mg drug product of aflibercept (AFL-2)-an anti-vascular endothelial growth factor agent-has established efficacy and safety in both diseases. In pivotal trials, a high-dose drug product (AFL-HD) using a formulation distinct from AFL-2 and delivering 8-mg aflibercept every 12 or 16 weeks (following initial monthly dosing) provided visual gains non-inferior to AFL-2 administered every 8 weeks (following initial monthly dosing) and comparable safety with fewer injections over 96 weeks. Free and bound aflibercept concentrations in plasma from 2744 participants in 16 clinical trials where aflibercept was administered intravitreally, subcutaneously, or intravenously were analyzed by population pharmacokinetic modeling. A semi-mechanistic model described the release of free aflibercept from the eye and its target-mediated elimination from plasma. The evaluated covariates (weight, age, sex, albumin, disease, racial classification, Japanese origin, renal and hepatic functions) resulted in only small numerical differences in systemic exposure. Ocular clearance (Q_E; characterizing the bidirectional transfer of free aflibercept between the eye and central compartment) was comparable across both diseases after adjusting for an age-dependent decrease. The change in drug product, and not just the dose increase, was responsible for a 39.4% slower Q_E and extended exposure in the ocular space for AFL-HD versus AFL-2. The median ocular concentrations of free aflibercept predicted at the end of the 8-week dosing interval for AFL-2 were typically reached 14 weeks after AFL-HD injections, versus 9-9.5 weeks if Q_E was identical for both drug products.