Macular Degeneration: Gaudreault J

Gaudreault J, Fei D, Beyer JC, Ryan A, Rangell L, Shiu V, Damico LA. · Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc., South San Francisco, California, USA. · Retina. · Pubmed #18046235 No free full text.

Abstract: PURPOSE: Ranibizumab (Lucentis) is a humanized antigen-binding fragment designed to inhibit all isoforms and active degradation products of vascular endothelial growth factor A (VEGF-A); it is in clinical development for the treatment of neovascular age-related macular degeneration (AMD). This study evaluated its pharmacokinetics (PK) and retinal distribution in rabbits when administered intravitreally (ITV). METHODS: A total of 27 New Zealand white rabbits received a single bilateral ITV injection of ranibizumab 625 muicrog/eye (Group 1, n = 24) or I-labeled ranibizumab 625 microg/eye, 22.5 microCi/eye (Group 2, n = 3). Ranibizumab concentration was determined in the vitreous, aqueous humor, and serum up to 60 days postdose by enzyme-linked immunosorbent assay in Group 1. Group 2 eyes were microautoradiographed on days 1-4. RESULTS: Ranibizumab has a terminal half-life of 2.9 days in the ocular compartments. Systemic exposure was low, measuring less than 0.01% of vitreous exposure when comparing AUC0-t values. Microautoradiography analysis demonstrated that ranibizumab penetrated all retinal layers, reaching the choriocapillaris on days 1, 2, and 4. CONCLUSIONS: This study demonstrates that following ITV injection, ranibizumab has a vitreous half-life of 2.9 days with minimal systemic exposure. Ranibizumab rapidly penetrates through the retina to reach the choroid, supporting its clinical development for neovascular AMD.

Lowe J, Araujo J, Yang J, Reich M, Oldendorp A, Shiu V, Quarmby V, Lowman H, Lien S, Gaudreault J, Maia M. · Department of BioAnalytical R&D, MS38, Genentech, Inc., One DNA Way, South San Francisco, CA 94080-4990, USA. · Exp Eye Res. · Pubmed #17714704 No free full text.

Abstract: Neovascular age-related macular degeneration (AMD) is the leading cause of blindness in older adults in the Western world. Ranibizumab (Lucentis), a humanized antibody fragment directed against vascular endothelial growth factor (VEGF-A), was recently approved by the US Food and Drug Administration (FDA) for the treatment of neovascular AMD. The objective of this study was to characterize the binding affinity and pharmacological activity of ranibizumab for 3 biologically active forms of VEGF-A: VEGF165, VEGF121, and VEGF110. The apparent equilibrium binding affinity of ranibizumab for VEGF-A molecules was determined by Biacore analysis; the biological activity of VEGF-A was demonstrated in a human umbilical vein endothelial cell (HUVEC) proliferation-inhibition assay. Inhibition of VEGF-A-induced vascular permeability by ranibizumab was assessed in vivo using hairless guinea pigs and a modified Miles assay. Ranibizumab was capable of binding to recombinant human VEGF165, VEGF121, and VEGF110 (KD < or = 192 pM), inhibiting VEGF-A-induced HUVEC proliferation in a concentration-dependent manner. Ranibizumab also exerted potent dose-dependent inhibition (IC(50) of 0.4-1.2 nM) of the vascular permeability-enhancing activity of VEGF165, VEGF121, and VEGF110 in the Miles assay. In conclusion, these results show that ranibizumab is capable of binding to and specifically inhibiting the activities of 3 biologically active forms of VEGF-A. As VEGF-A plays a pivotal role in the pathogenesis of neovascular AMD, ranibizumab activity, as demonstrated in this study, supports its clinical utility in the treatment of this disease.

Gaudreault J, Fei D, Rusit J, Suboc P, Shiu V. · Department of Pharmacokinetic, Genentech Inc., South San Francisco, CA 94080, USA. · Invest Ophthalmol Vis Sci. · Pubmed #15671306 links to  free full text

Abstract: PURPOSE: Ranibizumab (rhuFab V2; Lucentis, Genentech, South San Francisco, CA) is a humanized monoclonal antibody fragment designed to bind all forms of VEGF, thereby blocking vessel permeability and angiogenesis in neovascular age-related macular degeneration. This study evaluated the pharmacokinetic (PK) and serum bioavailability of ranibizumab after a single intravitreal (ITV) or intravenous (IV) dose in cynomolgus monkeys. METHODS: Monkeys received ranibizumab as either a bilateral ITV dose (500 or 2000 microg/eye; n = 6/group) or a single IV dose (1000 or 4000 microg/animal; n = 4/group). After ITV administration, ranibizumab concentrations were measured in several ocular compartments and in serum for 10 days and, after IV administration, for 48 hours. Pharmacokinetic parameters were estimated by compartmental and noncompartmental methods. RESULTS: Ranibizumab cleared in parallel from all ocular compartments, with a terminal half-life of approximately 3 days. It distributed rapidly to the retina (6-24 hours), and concentrations were approximately one third that in the vitreous. After ITV injection, bioavailability (F) was 50% to 60%. Serum concentrations were very low, reflecting wider distribution and faster clearance when ranibizumab reached the serum. After IV administration, the terminal half-life was approximately 0.5 day. CONCLUSIONS: This study demonstrates that ranibizumab has a PK profile that is favorable for its clinical use in treating neovascular AMD by monthly ITV injection.

Krzystolik MG, Afshari MA, Adamis AP, Gaudreault J, Gragoudas ES, Michaud NA, Li W, Connolly E, O'Neill CA, Miller JW. · Retina Service, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114, USA. · Arch Ophthalmol. · Pubmed #11879138 No free full text.

Abstract: OBJECTIVE: To evaluate the safety and efficacy of intravitreal injections of an antigen-binding fragment of a recombinant humanized monoclonal antibody directed toward vascular endothelial growth factor (rhuFab VEGF) in a monkey model of choroidal neovascularization (CNV). METHODS: In phase 1 of the study, each animal received intravitreal injections, 500 microg per eye, of rhuFab VEGF in one eye (prevention eye), while the contralateral eye received rhuFab VEGF vehicle (control eye) at 2-week intervals. On day 21, laser photocoagulation was performed to induce CNV. In phase 2, the vehicle-treated eye was crossed over and both eyes received 500 microg of rhuFab VEGF beginning 21 days following laser-induced injury at days 42 and 56. The eyes were monitored by ophthalmic examinations, color photographs, and fluorescein angiography. RESULTS: rhuFab VEGF did not cause any ocular hemorrhages. All eyes treated with rhuFab VEGF developed acute anterior chamber inflammation within 24 hours of the first injection that resolved within 1 week, and this inflammation was less severe with subsequent injections. The incidence of CNV, defined angiographically, was significantly lower in the prevention eyes than the control eyes (P<.001). Subsequent treatments were associated with less leakage in eyes with established CNV that were crossed over from the control eyes to the treatment eyes (P =.001). CONCLUSIONS: Intravitreal rhuFab VEGF injections prevented formation of clinically significant CNV in cynomolgus monkeys and decreased leakage of already formed CNV with no significant toxic effects. CLINICAL RELEVANCE: This study provides the nonclinical proof of principle for ongoing clinical studies of intravitreally injected rhuFab VEGF in patients with neovascular age-related macular degeneration.