Population Pharmacokinetics of Ranibizumab Delivered via the Port Delivery System Implanted in the Eye in Patients with Neovascular Age-Related Macular Degeneration.

Abstract

The port delivery system with ranibizumab (PDS) is designed to continuously deliver ranibizumab to maintain therapeutic drug concentrations in the vitreous of the eye for an extended duration. The PDS has been evaluated for the treatment of neovascular age-related macular degeneration in the Ladder (PDS 10, 40, and 100mg/mL, with refill exchanges as needed, versus monthly intravitreal ranibizumab 0.5mg), Archway (PDS 100mg/mL with 24-week refill exchanges, versus monthly intravitreal ranibizumab 0.5mg), and ongoing Portal (PDS 100mg/mL with 24-week refill exchanges) clinical trials. Data from Ladder, Archway, and Portal were used to develop a population pharmacokinetics (PK) model to estimate the ranibizumab release rate from the PDS implant, describe ranibizumab PK in serum and aqueous humor, and predict the concentration in vitreous humor. A model was developed to adequately describe the serum and aqueous humor PK data, as suggested by goodness-of-fit plots as well as visual predictive checks. In the final model, the first-order implant release rate was estimated to be 0.00654 (1/day), corresponding to a half-life of 106days, consistent with the implant release rate determined invitro. The model-predicted vitreous concentrations achieved with PDS 100mg/mL given every 24weeks were below the intravitreal peak concentration and above the intravitreal trough concentration of ranibizumab over the entire 24-week refill interval. The results demonstrate a durable release of ranibizumab from the PDS with a half-life of 106days, providing vitreous exposure to ranibizumab for at least 24weeks that is within the range of exposure for monthly intravitreal treatment.