12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ranibizumab products bind to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF 110. VEGF-A has been shown to cause neovascularization and leakage in models of ocular angiogenesis and vascular occlusion and is thought to contribute to pathophysiology of neovascular AMD, mCNV, DR, DME and macular edema following RVO. The binding of ranibizumab products to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.

12.2 Pharmacodynamics

Increased retinal thickness (i.e., center point thickness (CPT) or central foveal thickness (CFT)), as assessed by optical coherence tomography (OCT) is associated with neovascular AMD, mCNV, macular edema following RVO, and DME. Leakage from choroidal neovascularization (CNV) as assessed by fluorescein angiography (FA) is associated with neovascular AMD and mCNV. Microvascular retinal changes and neovascularization, as assessed by color fundus photography, are associated with diabetic retinopathy.

Neovascular (Wet) Age-Related Macular Degeneration

In Study AMD-3, CPT was assessed by time domain (TD)-OCT in 118 of 184 patients. TD-OCT measurements were collected at baseline, Months 1, 2, 3, 5, 8, and 12. In patients treated with ranibizumab, CPT decreased, on average, more than in the sham group from baseline through Month 12. CPT decreased by Month 1 and decreased further at Month 3, on average. In this study, CPT data did not provide information useful in influencing treatment decisions [see Clinical Studies (14.1)] .

In Study AMD-4, CFT was assessed by spectral domain (SD)-OCT in all patients; on average, CFT reductions were observed beginning at Day 7 following the first ranibizumab injection through Month 24. CFT data did not provide information capable of predicting final visual acuity results [see Clinical Studies (14.1)] .

In patients treated with ranibizumab, the area of CNV leakage, on average, decreased by Month 3 as assessed by FA. The area of CNV leakage for an individual patient was not correlated with visual acuity.

Macular Edema Following Retinal Vein Occlusion

On average, CPT reductions were observed in Studies RVO-1 and RVO-2 beginning at Day 7 following the first ranibizumab injection through Month 6. CPT was not evaluated as a means to guide treatment decisions [see Clinical Studies (14.2)] .

Diabetic Macular Edema

On average, CPT reductions were observed in Studies D-1 and D-2 beginning at Day 7 following the first ranibizumab injection through Month 36. CPT data did not provide information useful in influencing treatment decisions [see Clinical Studies (14.3)] .

Diabetic Retinopathy

Improvements from baseline in DR severity as assessed on fundus photography were observed in Studies D-1 and D-2 at Month 3 (first scheduled DR photographic assessment after randomization) through Month 36 [see Clinical Studies (14.4)] .

Myopic Choroidal Neovascularization

On average CFT reductions were observed as early as Month 1, and were greater in the ranibizumab groups compared to PDT [see Clinical Studies (14.5)] .

12.3 Pharmacokinetics

In patients with neovascular AMD, following monthly intravitreal administration of 0.5 mg ranibizumab, mean (±SD) maximum ranibizumab serum concentrations were 1.7 (± 1.1) ng/mL. These concentrations were below the concentration range of ranibizumab (11 to 27 ng/mL) that was necessary to inhibit the biological activity of VEGF-A by 50%, as measured in an in vitro cellular proliferation assay (based on human umbilical vein endothelial cells (HUVEC)). No significant change from baseline was observed in the mean plasma VEGF concentrations following three monthly 0.5 mg intravitreal injections. The maximum observed serum concentration was dose proportional over the dose range of 0.05 to 2 mg/eye. Serum ranibizumab concentrations in RVO and DME and DR patients were similar to those observed in neovascular AMD patients.

Based on a population pharmacokinetic analysis of patients with neovascular AMD, maximum serum concentrations are predicted to be reached at approximately 1 day after monthly intravitreal administration of ranibizumab 0.5 mg/eye. Based on the disappearance of ranibizumab from serum, the estimated average vitreous elimination half-life was approximately 9 days. Steady-state minimum concentration is predicted to be 0.22 ng/mL with a monthly dosing regimen. In humans, serum ranibizumab concentrations are predicted to be approximately 90,000-fold lower than vitreal concentrations.

In pharmacokinetic covariate analyses, 48% (520/1091) of patients had renal impairment (35% mild, 11% moderate, and 2% severe). Because the increases in plasma ranibizumab exposures in these patients are not considered clinically significant, no dosage adjustment is needed based on renal impairment status.