A Mechanistic and Translational Pharmacokinetic-Pharmacodynamic Model of Abicipar Pegol and Vascular Endothelial Growth Factor Inhibition

Abstract

Abicipar pegol (abicipar) is a novel DARPin therapeutic and highly potent vascular endothelial growth factor (VEGF) inhibitor intended for the treatment of neovascular age-related macular degeneration (nAMD). Here we develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for abicipar to guide dosing regimens in the clinic. The model incorporated abicipar-VEGF binding kinetics, VEGF expression levels, and VEGF turnover rates to describe the ocular and systemic PK data collected from the vitreous, aqueous humor (AH), choroid, retina, and serum of rabbits after a 1-mg abicipar intravitreal (IVT) dose. The model was translated to humans using human-specific mechanistic parameters and refitted to human serum and AH concentrations from patients with diabetic macular edema and nAMD. The model was then used to simulate 8-, 12-(quarterly), and 16-week dosing intervals in the clinic. Simulations of 2 mg abicipar IVT at 8-week or quarterly dosing in humans indicates minimum steady-state vitreal concentrations are maintained above both in vitro IC 50 and in vivo human IC 50 values. The model predicted virtually complete VEGF inhibition for the 8-week and quarterly dosing schedule during the 52-week treatment period. In the 16-week schedule, clinically significant VEGF inhibition was maintained during the 52-week period. The model quantitatively described abicipar-VEGF target engagement leading to rapid reduction of VEGF and a long duration of VEGF inhibition demonstrating the clinical feasibility of up to a 16-week dosing interval. Abicipar is predicted to reduce IVT dosing compared with other anti-VEGF therapies with the potential to lessen patient treatment burden. SIGNIFICANCE STATEMENTCurrent anti-VEGF treatments for neovascular age-related macular degeneration require frequent (monthly) intravitreal injections and monitoring, which increases patient burden. We developed a mechanistic pharmakinetic/pharmadynamic model to describe the interaction between abicipar (a novel VEGF inhibitor) and VEGF to evaluate the duration of action. The model demonstrates extended abicipar-VEGF target engagement leading to clinical feasibility of up to a 16-week dosing interval. Our model predicted that abicipar 8-week and quarterly dosing schedules maintain virtually complete VEGF inhibition during the 52-week period.

A DARPin targeting activated Mac-1 is a novel diagnostic tool and potential anti-inflammatory agent in myocarditis, sepsis and myocardial infarction

“…tumour therapy, inflammation, and imaging [10]. Due to these advantages, as well as high affinity and specificity binding to their target epitopes, DARPins are very attractive as diagnostic tools and therapeutic agents, and in fact the first DARPins have been successfully established as drugs in clinical applications such as neovascular age-related macular degeneration [50].…”

Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 1. THR-149

“…on the difference in trabecular mesh outflow or retinal blood flow between the two species. In the present case, though, there is no evidence that k 2 represents aqueous humor (AH)-to-plasma transfer since AH-to-plasma transfer rate constants have been reported either for small molecules or biologics that are significantly larger than our value of k 2 [17,18]. Extrapolation of k 2 to human based on trabecular mesh outflow thus doesn't seem appropriate.…”

“…Drug-target interaction can potentially modify the overall drug elimination and other researchers have very elegantly addressed the matter (see e.g. [16,17]). However, the impact of target binding on overall drug elimination can only become significant when the drug levels and the target concentration are of the same order of magnitude.…”

“…Le et al [16] described an integrated ocular-systemic model for the anti-factor D antigen-binding fragment (Fab) lampalizumab in the cynomolgus monkey which takes into account target mediated drug disposition, target turnover, and drug distribution across ocular tissues and systemic circulation. Also, Luu et al [17] reported a model for the anti-VEGF DARPin abicipar pegol that incorporates VEGF binding kinetics, VEGF expression levels, and VEGF turnover rates to describe ocular and systemic pharmacokinetic data in the rabbit. Buitrago et al [18] used a three-compartment pharmacokinetic model to assess plasma levels after IVT injection of the chemotherapy drug topotecan in rabbits.…”

Beyond Antibodies: The DARPin® Drug Platform

“…PEGylation of the VEGF-binding DARPin ® molecule produced the drug candidate MP0112 with an ocular half-life in rabbit of 6.6 days, almost double that of ranibizumab (3.5 days) [29] and maintained high potency. Based on a simple mathematical model, these parameters supported the possibility that dosing humans once every 12 weeks (q12w) should provide continuous, complete VEGF inhibition [29,30].…”