Plasma Pharmacokinetics of AL-4940, the Active Metabolite of Anecortave Acetate, Following Posterior Juxtascleral Injections in Patients with Age-Related Macular Degeneration

Abstract

Abstract: : Purpose: Anecortave acetate is an angiostatic agent in clinical trials for treatment of exudative age-related macular degeneration (AMD). Anecortave Acetate is administered as a posterior juxtascleral depot using a specially designed cannula. The purpose of the two studies described herein was to evaluate the systemic pharmacokinetics of AL-4940, the active metabolite of Anecortave Acetate, following posterior juxtascleral administration. Methods: In a Phase II study (C-98-03), sparse plasma samples were collected up to 6 weeks after injection in 22 classic AMD patients administered 3, 15 or 30 mg doses to the diseased eye every 6 months Patients in this study did not receive photodynamic therapy (PDT). In a separate Phase I study (C-00-41), more frequent plasma samples were obtained after injection in 12 classic and 22 occult AMD patients given two single 30-mg doses 6 months apart. In this study, patients with classic lesions received PDT, whereas occult patients did not. Plasma samples were assayed for AL-4940 by LC/MS/MS (quantitation limit 0.05 ng/mL). Results: In both studies plasma concentrations of AL-4940 were measurable out to 2 weeks after dosing. In the Phase II study of classic patients receiving 3, 15 and 30 mg, maximal observed plasma concentrations (Cmax) of AL-4940 were dose-proportional after the first dose (0.45 ± 0.27, 2.16 ± 1.47 and 3.93 ± 1.48 ng/mL), indicating linear, predictable pharmacokinetics. Plasma Cmax data from three subsequent doses showed a lack of accumulation (samples from later doses are currently being assayed and data will be presented). In the 30-mg Phase I study, AL-4940 Cmax values and area under the plasma concentration curves through 2 weeks (AUC_0-2wk) after the first dose in occult patients (no PDT) (mean 3.27 ± 1.46 ng/mL, AUC_0-2wk = 10.0 ± 3.1 ng*day/mL) were similar to those in classic patients (with PDT) (mean 4.27 ± 2.90 ng/mL, AUC_0-2wk = 12.9 ± 6.2 ng*day/mL). The mean plasma Cmax following the second dose indicated no accumulation. Conclusions: Plasma concentrations of AL-4940 were low and were quantifiable for about 2 weeks of the 6-month dosing interval. No accumulation was evident in plasma following multiple injections. The pharmacokinetic properties of AL-4940 were linear and predictable and were not altered by PDT.

Keywords: age-related macular degeneration • retina • injection