Intraocular Pharmacokinetics of 10-fold Intravitreal Ranibizumab Injection Dose in Rabbits

Abstract

Purpose:To investigate intraocular pharmacokinetics of 10-fold dose of intravitreally injected ranibizumab compared with the conventional dose in an experimental model. Methods:Ranibizumab 30 μL at 10 mg/mL (conventional) and 100 mg/mL (10-fold) doses was injected separately into each eye of 28 rabbits. Ranibizumab concentrations in the aqueous humor, vitreous, and retina were estimated at each time period after injection, using enzyme-linked immunosorbent assay. The pharmacokinetic properties of ranibizumab were determined using a one-compartment model in all three ocular tissues. The time-concentration profile and predictive trends were plotted to determine drug efficacy in the retina.Results: Maximum concentrations after conventional and 10-fold dosing were observed in the retina at 1 and 4 days after injection, respectively. The half-life of ranibizumab after conventional and 10-fold dosing did not differ in the anterior chamber and vitreous, whereas the half-life was prolonged approximately twice with the 10-fold dose in the retina (36.74 h vs. 76.85 h) and serum (91.93 h vs. 179.01 h). Similarly, the estimated time for ranibizumab concentration in the retina over 27 ng/mL (minimum effective concentration of ranibizumab) was prolonged approximately twice with the 10-fold dose (1315 h [55 days] vs. 2393 h [100 days]). No adverse effects were observed in either group. Conclusions:The retinal half-life and concentration of ranibizumab in rabbit eyes were increased approximately twice after a 10-fold dose compared with the conventional dose. This finding indicates a possibility to lengthen the injection interval to improve the efficacy of ranibizumab in human eyes.Translational Relevance: Our results highlight the potential for clinical application of a high-dose (10-fold) of anti-VEGF agents to prolong the intravitreal injection intervals, simultaneously improving the drug efficacy.

Biomimetic, Injectable, and Self-Healing Hydrogels with Sustained Release of Ranibizumab to Treat Retinal Neovascularization

“…Approximately 100 μL of aqueous humor was collected through a 30 gauge syringe at the limbus before treatment and at different time intervals (3 and 7 days and weekly thereafter) after treatment. The concentration of ranibizumab present in the samples was determined with an indirect enzyme-linked immunosorbent assay (ELISA) using the recombinant human VEGF-A (R&D Systems, Minneapolis, MN, USA) according to the previously developed methods. , Aqueous VEGF concentrations were measured with a human VEGF Quantikine ELISA Kit (R&D Systems, Minneapolis, MN, USA) according to the manufacturer’s instruction. Finally, the concentrations were calculated from a standard curve and the lower limits of quantitation (LLOQs) were 15.0 and 15.6 pg/mL, respectively.…”

Ocular Drug Delivery to the Retina: Current Innovations and Future Perspectives

“…The READ-3 study group that evaluated diabetic macular edema suggested that conventional 0.5 mg and higher 2 mg doses of ranibizumab did not alter the 24 months visual improvements [ 54 ]. In a pre-clinical animal study, Kim et al administered a 10-fold dose of ranibizumab in rabbit eyes that resulted in a two-fold increase in retinal half-life and long-lasting effective concentration in the retinal compartment, without any adverse local or systemic effects [ 55 ]. The contradictory results of dose escalation suggest that further experiments and clinical trials should be conducted.…”

Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications

“…An intravitreal injection of high-dose anti-VEGF agents might prolong the intravitreal injection intervals and improve drug efficacy. Using rabbits, Kim et al showed that a two-fold increase in retinal half-life and prolonged effective concentration of ranibizumab in retina when administered a 10-fold dose of ranibizumab with good safety in rabbit eyes [ 149 ]. Currently, phase 3 clinical trials are underway in DME (PHOTON; NCT04429503) and nAMD (PULSAR; NCT04423718).…”