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Mechanism of Action

Ranibizumab binds to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF₁₁₀. VEGF-A has been shown to cause neovascularization and leakage in models of ocular angiogenesis and vascular occlusion, and is thought to contribute to the progression of neovascular AMD and macular edema following RVO. The binding of ranibizumab 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.

Pharmacodynamics

Increased center point thickness (CPT) as assessed by optical coherence tomography (OCT) is associated with neovascular AMD and macular edema following RVO. Leakage from choroidal neovascularization (CNV) as assessed by fluorescein angiography is associated with neovascular AMD.

Neovascular (Wet) Age-Related Macular Degeneration

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

In patients treated with LUCENTIS (ranibizumab injection) , the area of vascular leakage, on average, decreased by Month 3 as assessed by fluorescein angiography. The area of vascular 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 LUCENTIS (ranibizumab injection) injection through Month 6. CPT was not evaluated as a means to guide treatment decisions [see Clinical Studies].

Pharmacokinetics

In animal studies, following intravitreal injection, ranibizumab was cleared from the vitreous with a half-life of approximately 3 days. After reaching a maximum at approximately 1 day, the serum concentration of ranibizumab declined in parallel with the vitreous concentration. In these animal studies, systemic exposure of ranibizumab is more than 2000-fold lower than in the vitreous.

In patients with neovascular AMD, following monthly intravitreal administration, maximum ranibizumab serum concentrations were low (0.3 ng/mL to 2.36 ng/mL). These levels were below the concentration of ranibizumab (11 ng/mL to 27 ng/mL) thought to be necessary to inhibit the biological activity of VEGF-A by 50%, as measured in an in vitro cellular proliferation assay. The maximum observed serum concentration was dose proportional over the dose range of 0.05 to 1 mg/eye. Serum ranibizumab concentrations in RVO patients were similar to those observed in neovascular AMD patients.

Based on a neovascular AMD population pharmacokinetic analysis, maximum serum concentrations of 1.5 ng/mL are predicted to be reached at approximately 1 day after monthly intravitreal administration of LUCENTIS (ranibizumab injection) 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.

Clinical Studies

Neovascular (Wet) Age-Related Macular Degeneration (AMD)

The safety and efficacy of LUCENTIS (ranibizumab injection) were assessed in three randomized, double-masked, sham- or active-controlled studies in patients with neovascular AMD. A total of 1323 patients (LUCENTIS (ranibizumab injection) 879, Control 444) were enrolled in the three studies.

Studies AMD-1 andAMD-2

In Study AMD-1, patients with minimally classic or occult (without classic) CNV lesions received monthly LUCENTIS (ranibizumab injection) 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections. Data are available through Month 24. Patients treated with LUCENTIS (ranibizumab injection) in Study AMD-1 received a mean of 22 total treatments out of a possible 24 from Day 0 to Month 24.

In Study AMD-2, patients with predominantly classic CNV lesions received one of the following: 1) monthly LUCENTIS (ranibizumab injection) 0.3 mg intravitreal injections and sham PDT; 2) monthly LUCENTIS (ranibizumab injection) 0.5 mg intravitreal injections and sham PDT; or 3) sham intravitreal injections and active verteporfin PDT. Sham PDT (or active verteporfin PDT) was given with the initial LUCENTIS (ranibizumab injection) (or sham) intravitreal injection and every 3 months thereafter if fluorescein angiography showed persistence or recurrence of leakage. Data are available through Month 24. Patients treated with LUCENTIS (ranibizumab injection) in Study AMD-2 received a mean of 21 total treatments out of a possible 24 from Day 0 through Month 24.

In both studies, the primary efficacy endpoint was the proportion of patients who maintained vision, defined as losing fewer than 15 letters of visual acuity at 12 months compared with baseline. Almost all LUCENTIS (ranibizumab injection) -treated patients (approximately 95%) maintained their visual acuity. 34%-40% of LUCENTIS (ranibizumab injection) -treated patients experienced a clinically significant improvement in vision, defined as gaining 15 or more letters at 12 months.

The size of the lesion did not significantly affect the results. Detailed results are shown in the Table 3, Table 4, and Figure 1 below.

Table 3 : Outcomes at Month 12 and Month 24 in Study AMD-1

Table 4: Outcomes at Month 12 and Month 24 in Study AMD-2

Figure 1 : Mean Change in Visual Acuity from Baseline to Month 24 in Study AMD-1 and Study AMD-2

Patients in the group treated with LUCENTIS (ranibizumab injection) had minimal observable CNV lesion growth, on average. At Month 12, the mean change in the total area of the CNV lesion was 0.1-0.3 DA for LUCENTIS (ranibizumab injection) versus 2.3-2.6 DA for the control arms. At Month 24, the mean change in the total area of the CNV lesion was 0.3-0.4 DA for LUCENTIS (ranibizumab injection) versus 2.9-3.1 DA for the control arms.

Study AMDS

Study AMD-3 was a randomized, double-masked, sham-controlled, two-year study designed to assess the safety and efficacy of LUCENTIS (ranibizumab injection) in patients with neovascular AMD (with or without a classic CNV component). Data are available through Month 12. Patients received LUCENTIS (ranibizumab injection) 0.3 mg or 0.5 mg intravitreal injections or sham injections once a month for 3 consecutive doses, followed by a dose administered once every 3 months for 9 months. A total of 184 patients were enrolled in this study (LUCENTIS (ranibizumab injection) 0.3 mg, 60; LUCENTIS (ranibizumab injection) 0.5 mg, 61; sham, 63); 171 (93%) completed 12 months of this study. Patients treated with LUCENTIS (ranibizumab injection) in Study AMD-3 received a mean of 6 total treatments out of a possible 6 from Day 0 through Month 12.

In Study AMD-3, the primary efficacy endpoint was mean change in visual acuity at 12 months compared with baseline (see Figure 2). After an initial increase in visual acuity (following monthly dosing), on average, patients dosed once every three months with LUCENTIS (ranibizumab injection) lost visual acuity, returning to baseline at Month 12. In Study AMD-3, almost all LUCENTIS (ranibizumab injection) -treated patients (90%) maintained their visual acuity at Month 12.

Figure 2 : Mean Change in Visual Acuity from Baseline to Month 12 in Study AMD-3

Macular Edema Following Retinal Vein Occlusion (RVO)

The safety and efficacy of LUCENTIS (ranibizumab injection) were assessed in two randomized, double-masked, one-year studies in patients with macular edema following RVO. Sham controlled data are available through Month 6. Patient age ranged from 20 to 91 years, with a mean age of 67 years. A total of 789 patients (LUCENTIS (ranibizumab injection) 0.3 mg, 266 patients; LUCENTIS (ranibizumab injection) 0.5 mg, 261 patients; sham, 262 patients) were enrolled, with 739 (94%) patients completing through Month 6. All patients completing Month 6 were eligible to receive LUCENTIS (ranibizumab injection) injections guided by pre-specified re-treatment criteria until the end of the studies at Month 12.

In Study RVO-1, patients with macular edema following branch or hemi- RVO, received monthly LUCENTIS (ranibizumab injection) 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections for 6 months. All patients were eligible for rescue laser treatment beginning at Month 3 of the 6 month treatment period. Rescue laser treatment was given to 26 of 131 (20%) patients treated with 0.5 mg LUCENTIS (ranibizumab injection) and 72 of 132 (55%) patients treated with sham.

In Study RVO-2, patients with macular edema following central RVO received monthly LUCENTIS (ranibizumab injection) 0.3 mg or 0.5 mg intravitreal injections or monthly sham injections for 6 months.

At Month 6, after monthly treatment with 0.5 mg LUCENTIS (ranibizumab injection) , the following clinical results were observed:

Table 5 : Percentage of Patients with Gain of ≥ 15 letters in Visual Acuity from Baseline to Month 6 in Study RVO-1 and Study RVO-2

Figure 3 : Mean Change in Visual Acuity from Baseline to Month 6 in Study RVO-1 and Study RVO-2

Last reviewed on RxList: 7/21/2010
This monograph has been modified to include the generic and brand name in many instances.