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Stefan Yohe, Katie Maass, Judit Horvath, Jennifer Rea, Giulio Barteselli, Shrirang Ranade; In vitro characterization of ranibizumab release from the Port Delivery System. Invest. Ophthalmol. Vis. Sci. 2021;62(8):192.
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The Port Delivery System with ranibizumab (PDS) is an innovative, investigational drug delivery system designed for the continuous delivery of ranibizumab into the vitreous via diffusion-mediated release kinetics. Target ranibizumab release rates were selected by leveraging clinical and pharmacokinetic (PK) data from trials with intravitreal ranibizumab injections. In vitro testing was used to verify release rates with different ranibizumab concentrations before the phase 2 Ladder trial (NCT02510794) of the PDS in patients with neovascular age-related macular degeneration.
To mimic the clinical setting in vitro, implants were filled per the clinical “Instructions for Use.” Implants with ranibizumab were regularly transferred to new buffer-containing vials to mimic ocular ranibizumab clearance and to sustain similar release kinetics.A Bradford assay was used to measure released ranibizumab concentrations in each buffer-containing vial. Concentration data were used to calculate an average daily ranibizumab release rate. The activity of ranibizumab released from implants was determined by a Biacore assay. Results from this assay were used to determine a percentage of active ranibizumab, as well as an active ranibizumab release rate. Release rate data were fit using an exponential model to mimic the expected release kinetics of diffusion and compared to predicted release rate kinetics.
Release profiles of the PDS with 3 ranibizumab concentrations (10, 40, and 100 mg/mL) were determined. At day 3.5, mean (SD) ranibizumab release rates were 1.75 (0.07), 6.42 (0.35), and 16.69 (0.67) µg/day for PDS 10, 40, and 100 mg/mL, respectively. At month 6, respective mean (SD) release rates were 1.68 (0.05) and 4.16 (0.05) µg/day for PDS 40 and 100 mg/mL. PDS 100 mg/mL released 73% (SD, 1.92) of drug by month 6. Active drug release from PDS 100 mg/mL was 98%, 88%, and 75% at day 3.5, month 6, and month 12, respectively. Consistent with these data, Ladder serum PK data showed that PDS 100 mg/mL released ranibizumab through at least month 16.
The PDS was designed to release ranibizumab over an extended period of time. Ranibizumab release from the PDS implant was demonstrated to be highly predictable and tunable based on a simple diffusion model. These findings support the median time to first refill of 15.8 months in Ladder PDS 100 mg/mL patients.
This is a 2021 ARVO Annual Meeting abstract.
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