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Tom Wilde, Valeriu Damian; In Silico Mechanistic Model for Understanding Intravitreal Dosing Frequency of Anti-VEGF Therapies. Invest. Ophthalmol. Vis. Sci. 2014;55(13):601.
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While intravitreally injected anti-VEGF (vascular endothelial growth factor) therapy has proven efficacious against wet age-related macular degeneration (AMD), the pharmacokinetic/ pharmacodynamic (PK/PD) relationship and its connection to dosing frequency is still not well understood. To address this gap, a mechanistic model was built which incorporates ocular physiology, PK/distribution, VEGF production, and VEGF binding kinetics.
A compartmental ocular model was built using parameters obtained or estimated from literature references. These parameters include VEGF binding kinetics to both VEGF receptor and anti-VEGF therapies, as well as ocular PK and distribution parameters for VEGF and anti-VEGF therapies. VEGF production was not available in the literature, but was estimated from ocular VEGF levels in AMD patients.
Following parameterization of the model and without further calibration or fitting, simulations for three anti-VEGF therapies (ranibizumab, bevacizumab, and aflibercept) were performed using standard clinical doses. Results of these simulations showed that unbound VEGF levels and VEGF receptor occupancy do not return to baseline until approximately one month post-dose for ranibizumab and bevacizumab and two months post-dose for aflibercept, which is consistent with the recommended clinical dosing regimens for wet AMD maintenance for these therapies.
By integrating available knowledge of ocular physiology, PK and distribution, and binding kinetics, this mechanistic anti-VEGF model demonstrates that efficacious dosing regimens for three marketed AMD treatments can be correlated to simulated VEGF receptor occupancy. In addition to representing a significant advance in current anti-VEGF PK/PD understanding, this model could aid development of novel anti-VEGF therapies by predicting efficacious doses early in development and guiding clinical dosing strategies.
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