Ranibizumab

Ranibizumab is a humanised recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor A (VEGF-A). It binds with high affinity to the VEGF-A isoforms (e.g. VEGF₁₁₀, VEGF₁₂₁ and VEGF₁₆₅), thereby preventing binding of VEGF-A to its receptors VEGFR-1 and VEGFR-2. Binding of VEGF-A to its receptors leads to endothelial cell proliferation and neovascularisation, as well as vascular leakage, all of which are thought to contribute to the progression of the neovascular form of age-related macular degeneration, pathologic myopia and CNV or to visual impairment caused by either diabetic macular oedema or macular oedema secondary to RVO in adults and retinopathy of prematurity in preterm infants.

Following monthly intravitreal administration of ranibizumab to patients with neovascular AMD, serum concentrations of ranibizumab were generally low, with maximum levels (C_max) generally below the ranibizumab concentration necessary to inhibit the biological activity of VEGF by 50% (11-27 ng/ml, as assessed in an in vitro cellular proliferation assay). C_max was dose proportional over the dose range of 0.05 to 1.0 mg/eye. Serum concentrations in a limited number of DME patients indicate that a slightly higher systemic exposure cannot be excluded compared to those observed in neovascular AMD patients. Serum ranibizumab concentrations in RVO patients were similar or slightly higher compared to those observed in neovascular AMD patients.

Based on analysis of population pharmacokinetics and disappearance of ranibizumab from serum for patients with neovascular AMD treated with the 0.5 mg dose, the average vitreous elimination half-life of ranibizumab is approximately 9 days. Upon monthly intravitreal administration of ranibizumab 0.5 mg/eye, serum ranibizumab C_max , attained approximately 1 day after dosing, is predicted to generally range between 0.79 and 2.90 ng/ml, and C_min is predicted to generally range between 0.07 and 0.49 ng/ml. Serum ranibizumab concentrations are predicted to be approximately 90,000-fold lower than vitreal ranibizumab concentrations.

Patients with renal impairment

No formal studies have been conducted to examine the pharmacokinetics of ranibizumab in patients with renal impairment. In a population pharmacokinetic analysis of neovascular AMD patients, 68% (136 of 200) of patients had renal impairment (46.5% mild [50-80 ml/min], 20% moderate [30-50 ml/min], and 1.5% severe [<30 ml/min]). In RVO patients, 48.2% (253 of 525) had renal impairment (36.4% mild, 9.5% moderate and 2.3% severe). Systemic clearance was slightly lower, but this was not clinically significant.

Hepatic impairment

No formal studies have been conducted to examine the pharmacokinetics of ranibizumab in patients with hepatic impairment.

Paediatric population

Following intravitreal administration of ranibizumab to preterm infants with ROP at a dose of 0.2 mg (per eye), serum ranibizumab concentrations were higher than those observed in neovascular AMD adult patients receiving 0.5 mg in one eye. Based on a population pharmacokinetic analysis, the differences in C_max and AUC_inf were approximately 16-fold and 12-fold higher, respectively. The apparent systemic half-life was approximately 6 days. A PK/PD analysis showed no clear relationship between systemic ranibizumab concentrations and systemic VEGF concentrations.

Bilateral intravitreal administration of ranibizumab to cynomolgus monkeys at doses between 0.25 mg/eye and 2.0 mg/eye once every 2 weeks for up to 26 weeks resulted in dose-dependent ocular effects.

Intraocularly, there were dose-dependent increases in anterior chamber flare and cells with a peak 2 days after injection. The severity of the inflammatory response generally diminished with subsequent injections or during recovery. In the posterior segment, there were vitreal cell infiltration and floaters, which also tended to be dose-dependent and generally persisted to the end of the treatment period. In the 26-week study, the severity of the vitreous inflammation increased with the number of injections. However, evidence of reversibility was observed after recovery. The nature and timing of the posterior segment inflammation is suggestive of an immune-mediated antibody response, which may be clinically irrelevant. Cataract formation was observed in some animals after a relatively long period of intense inflammation, suggesting that the lens changes were secondary to severe inflammation. A transient increase in post-dose intraocular pressure was observed following intravitreal injections, irrespective of dose.

Microscopic ocular changes were related to inflammation and did not indicate degenerative processes. Granulomatous inflammatory changes were noted in the optic disc of some eyes. These posterior segment changes diminished, and in some instances resolved, during the recovery period.

Following intravitreal administration, no signs of systemic toxicity were detected. Serum and vitreous antibodies to ranibizumab were found in a subset of treated animals.

No carcinogenicity or mutagenicity data are available.

In pregnant monkeys, intravitreal ranibizumab treatment resulting in maximal systemic exposures 0.9-7-fold a worst case clinical exposure did not elicit developmental toxicity or teratogenicity, and had no effect on weight or structure of the placenta, although, based on its pharmacological effect ranibizumab should be regarded as potentially teratogenic and embryo-/foetotoxic.

The absence of ranibizumab-mediated effects on embryo-foetal development is plausibly related mainly to the inability of the Fab fragment to cross the placenta. Nevertheless, a case was described with high maternal ranibizumab serum levels and presence of ranibizumab in foetal serum, suggesting that the anti-ranibizumab antibody acted as (Fc region containing) carrier protein for ranibizumab, thereby decreasing its maternal serum clearance and enabling its placental transfer. As the embryo- foetal development investigations were performed in healthy pregnant animals and disease (such as diabetes) may modify the permeability of the placenta towards a Fab fragment, the study should be interpreted with caution.