Pharmacokinetics and Metabolism of Anecortave Acetate in Animals and Humans
Section snippets
Pharmacokinetics in Animals
In a variety of in vitro models, anecortave acetate effectively inhibited angiogenesis. This effect is thought to be related to the ability of anecortave acetate to suppress extracellular proteinase expression, an activity required for initiation of new blood vessel growth, to inhibit induction of vascular endothelial growth factor (VEGF) expression and production, and to block proliferation of VEGF-stimulated human retinal microvascular endothelial cells (HRMEC).2, 3, 6, 12, 13 In HRMEC
Pharmacokinetics in AMD Patients
The initial assessment of human exposure and pharmacokinetics of anecortave acetate by the PJD route was part of a phase II multiple-dose study (C-98-03). This study was a double-masked, randomized, multicenter, placebo-controlled, safety and efficacy trial in AMD patients. Patients were to be at least 50 years of age, and have a diagnosis of exudative AMD. A subset of patients at four study centers participated in the pharmacokinetic blood sampling. There were no special inclusion or exclusion
Metabolism of Anecortave Acetate
The biotransformation of anecortave acetate has been studied in rats, cynomolgus monkeys, and humans using carbon-14 labeled drug. Anecortave acetate is rapidly hydrolyzed by esterases to the active anecortave desacetate. In vitro and in vivo metabolism studies have shown that anecortave desacetate undergoes extensive metabolism similar to cortisol. In humans and monkeys, all metabolites circulating in plasma are in the form of glucuronide conjugates, with the exception of active anecortave
In Vitro Protein Binding
Plasma protein binding was determined using 14C-anecortave desacetate in vitro by ultrafiltration techniques at concentrations of 10, 30, 100, and 300 ng/ml. The results showed that anecortave desacetate binds moderately to plasma proteins, and that the binding was independent of the concentration range studied. The mean percent of 14C-anecortave desacetate bound to human plasma proteins was 93.5 ± 0.8% (range 92.6–94.6%). It is unlikely that anecortave desacetate will participate in drug–drug
Age/Elderly
All pharmacokinetic studies involving PJD administration were performed in AMD patients. Accordingly, all pharmacokinetic data presented represent the elderly and no special elderly pharmacokinetic studies were performed.
Gender
The effect of gender was evaluated by subgroup analysis of AMD patients in several studies. The results showed that there were no apparent differences associated with sex in the plasma pharmacokinetics of anecortave desacetate or its metabolites (AL-38508 and AL-38512
Discussion
Early preclinical studies of the ocular pharmacokinetics and distribution of anecortave acetate suspension revealed that bioavailability of active anecortave desacetate to the retina and choroid were inadequate by common systemic and periocular routes of administration. A cannula technique was developed in animals to dose a posterior juxtascleral depot with a high success rate in rabbits and monkeys. A counter pressure device was added to the technique to control the reflux of suspension from
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Cited by (14)
Effect of choroidal blood flow on transscleral retinal drug delivery using a porous medium model
2012, International Journal of Heat and Mass TransferVision and the hypothalamus
2010, OptometryCitation Excerpt :The current and future use of cortisol-related pharmaceutical agents can be well illustrated with anecortave acetate, a synthetic analog of cortisol acetate.55 The most notable properties of anecortave acetate are its being angiostatic, without having the glucocorticoid receptor–mediated effects typical of corticol.56 Currently, there is a clinical trial evaluating the effectiveness of anecortave acetate in arresting the progression of dry age-related macular degeneration in patients who are at risk for progressing to wet age-related macular degeneration.
Introduction
2007, Survey of OphthalmologyPreclinical Efficacy of Anecortave Acetate
2007, Survey of OphthalmologyCitation Excerpt :A specially designed cannula was used to administer anecortave acetate as a single posterior juxtascleral deposit for transcleral delivery immediately after subretinal implantation of FGF2. This route of administration mimics that used in the clinical investigation of anecortave acetate for CNV associated with AMD.9 CNV was detected in only 2 of 8 animals receiving as little as 0.5 mg and 3 of 8 animals receiving 2 mg anecortave acetate compared to 8 of 10 of the animals receiving vehicle.
Posterior Juxtascleral Depot Administration of Anecortave Acetate
2007, Survey of OphthalmologyCitation Excerpt :Preclinical data clearly demonstrate that direct contact of the drug bolus with the external surface of the sclera is absolutely necessary for a successful administration of anecortave acetate and essential for therapeutic concentrations to reach the target tissues (Fig. 2). Studies in rabbits show that therapeutic concentrations (≥0.1 μm) of drug can be found in the choroid and retina for as long as 24 weeks when anecortave acetate is delivered into a posterior juxtascleral depot.5 However, incorrect delivery results in inadequate concentration of the drug in the choroid and retina, making it clear that correct placement of the drug is essential for getting therapeutic concentrations to the target tissues.
Preclinical Safety of Anecortave Acetate
2007, Survey of OphthalmologyCitation Excerpt :Consistent with the single-dose PJD studies, there was transient, mild-to-moderate conjunctival hyperemia associated with PJD administration and generally minimal to mild periscleral inflammation adjacent to the drug depot. Topical ocular administration of anecortave acetate delivered effective drug levels to anterior segment tissues.1–4 Three- and twelve-month safety studies were conducted in rabbits, and a 12-month study was performed in monkeys to determine the safety of topical ocular administration of anecortave acetate.
The authors are employees of Alcon Research, Ltd., Fort Worth, TX.