Ranibizumab intravitreal injection

Lucentis contains ranibizumab and is available for intravitreal injection. It is a vascular endothelial growth factor inhibitor indicated for the treatment of neovascular (wet) age-related macular degeneration. Unlike verteporfin, which is used in photodynamic treatment of age-related macular degeneration, ranibizumab does not require activation by local irradiation using non-thermal red light. 

Lucentis Ranibizumab Genentech/Novartis Marketed product Exudative AMD Intravitreal injection... 

Two primary mechanisms of vitreal drug distribution and elimination are (i) diffusion from the lens region toward the retina with elimination via the retina-choroid-sclera and (ii) anterior diffusion with elimination via the hyaloid membrane and posterior chamber (18). Distribution to the retina from an intravitreal injection site is relatively slow, considering juxtaposition of the vitreous and retina, with the time for maximum drug concentration (tmax) in retina typically achieved at 4 to 12 hours, and reflects the inefficiency of diffusion over the distances encountered within the vitreous body. For example, ranibizumab, an ocular specific monoclonal VEGF antibody, distributes to the retina with of 6 to 24 hours. While relatively rapid therapeutically, this is slow compared with the rate of redistribution in stirred compartments. (249). 

The FDA approved intraocular injections include miotics, triamcinolone acetonide, pegaptanib sodium, ranibizumab, formivirsen sodium, viscoelastics and viscoadherents, and an antiviral agent for intravitreal injection. There are many small and large molecules currently in clinical trials that are delivered via intravitreal injection for the treatment of a variety of retinal diseases with a large area of focus on the treatment of AMD and macular edema. 

Safety. Animal studies have shown that ranibizumab is a safe agent for intravitreal injection. In cynomolgus monkeys, intravitreal injections of 500 pg of ranibizumab at two-week intervals in a laser-induced CNV model (13) or in normal monkey eyes did not show any significant adverse effects (14). However, mild side effects of the injections were seen. All eyes treated with ranibizumab developed acute anterior chamber inflammation within 24 hours of the first intravitreal injection (13). In contrast, eyes injected with vehicle alone showed minimal or no inflammation. The inflammation resolved within one week, and the inflammatory response was less pronounced after subsequent intravitreal ranibizumab injections. Also, animal studies have shown that ranibizumab has no effect on electroretinography, including visually evoked potentials. 

Pharmacodynamics. Since ranibizumab is delivered via an intravitreal injection, studies were undertaken to determine if the drug could cross the neural retina and access the subretinal space where the CNV lesions are located. A study in rhesus monkeys demonstrated that 25 pg in 50 pL of Fab antibody fragment diffused through the neural retina to the retinal pigment epithelial layer after one hour and persisted in this location for up to seven days (10). The half-life in the vitreous was 3.2 days. These data are consistent with the results of a pharmacokinetic study done by a noninvasive fluorophotometric method that showed that fluorescein-labeled ranibizumab disappeared from the vitreous with a mean terminal half-life of 2.9 days and a mean residence time of 4.2 days (11). 

Since VEGF plays an important role in other parts of the body, especially the cardiovascular system, systemic exposure was evaluated in preclinical studies. In monkey experiments, systemic exposure to ranibizumab was low, with plasma concentrations of the Fab antibody remaining below the limit of quantitation (<7.8 ng/mL) (10). Levels of plasma ranibizumab are highest on day one after injection and decrease rapidly by day seven (13). The ranibizumab antigen assay showed that the average detectable drug level in the vitreous was 32 ng/mL after the first injection and increased with subsequent injections (13). Thus, intravitreal injection of ranibizumab does not appear to lead to significant systemic levels. 

Study FVF1770g was a Phase I, open-label, dose-escalation trial of a single intravitreal injection of ranibizumab in subjects with new or recurrent CNV caused by exudative AMD. 

Chun DW, Heier JS, Topping TM et al. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant macular edema. Ophthalmology 2006 113(10) 1706-1712. 

Ranibizumab (Lucentisj 2006 Humanized 48 3-9 days from vitreous humor intravitreal injection (low serum concentrations) Vascular endothelial growth factor Wet-type macular degeneration... 

Sensory systems Eyes A transient increase in intraocular pressure has also been reported 0-30 minutes after intravitreal injections. In one study intraocular pressure rose as early as 5 seconds after intravenous injection of ranibizumab [11 ]. The mean pressure after 5 seconds was 44 (range 22-59) mmHg it was higher in eyes with shorter axial lengths. 

Gismondi M, Salati C, Salvetat ML, Zeppieri M, Brusini P. Short-term effect of intravitreal injection of ranibizumab (Lucentis) on intraocular pressure. J Glaucoma 2009 18 658-61. 

Retinal pigment epithelium tears can complicate exudative age-related macular degeneration or its treatment. An 81-year-old woman with retinal angiomatous proliferation and pigment epithelial detachment had a retinal pigment epithelial tear 10 days after an intravitreal injection of ranibizumab [12 ]. 

Administration is intravenous, subcutaneous or intramuscular. Ranibizumab is an exception in that it is injected intravitreally into the eye. 

In a randomized controlled trial in patients with diabetic macular edema who were randomised to intravitreal ranibizumab 0.5 mg, focal or grid laser, and a combination of these interventions, there was one serious adverse event (a stroke in a high-risk patient), which was presumed to be unrelated to the use of ranibizumab because it occurred 6 weeks after the injection [10 ]. There was no difference in blood pressure. Eight patients across the groups had vitreous hemorrhages, and in one patient it was combined with worsening of the macular edema, while in the others it was mild and had cleared at 6 months. 

Otsuka K, Imai H, Shimoyama T, Nagai T, Honda S, Azumi A. Recurrence of macular hole retinal detachment after intravitreal ranibizumab injection for the treatment of choroidal neovascularization from the remaining macular hole edge. Case Rep Ophthalmol 2012 3(3) 424-7. 

Joshi L, Morarji J, Tomkins-Netzer O, Lightman S, Taylor SRJ. Rhizobium radiobacter endophthalmitis following intravitreal ranibizumab injection. Case Rep Ophthalmol 2012 3(3) 283-5. 

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