Pharmacokinetics and Metabolism of Anecortave Acetate in Animals and Humans

doi:10.1016/j.survophthal.2006.11.002

Survey of Ophthalmology

Volume 52, Issue 1, Supplement, January 2007, Pages S49-S61

https://doi.org/10.1016/j.survophthal.2006.11.002 Get rights and content

Abstract

The ocular delivery of anecortave acetate was tested in preclinical and clinical pharmacokinetic and metabolism studies. Results of initial studies led to the design of a new cannula that could effectively deliver anecortave acetate as a posterior juxtascleral depot, providing adequate retinal and choroidal drug concentrations for up to 6 months after a single administration. A counter-pressure device was designed to prevent drug reflux during and immediately after posterior juxtascleral depot administration. Pharmacokinetic studies support the effectiveness of these devices. Anecortave acetate is rapidly hydrolyzed by esterases to pharmacologically active anecortave desacetate, and is further reductively metabolized to one major and several minor products that circulate as glucuronide conjugates. Low levels of these anecortave acetate metabolites were detectable for only approximately 2 weeks in the plasma after a 15-mg posterior juxtascleral depot administration to age-related macular degeneration patients. Studies show that posterior juxtascleral depot administration of anecortave acetate is an effective, minimally invasive method of delivering this drug to the choroid and retina.

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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Effect of choroidal blood flow on transscleral retinal drug delivery using a porous medium model
2012, International Journal of Heat and Mass Transfer
Transscleral drug delivery is one of the methods of depositing drug in the posterior segment (comprising retina, choroid, sclera and macula) of the human eye, to treat diseases such as age related macular degeneration (AMD). In this study, the effect of choroidal blood flow on transscleral drug delivery to the retina is investigated using a porous medium model of the sclera and the choroid. A two-dimensional geometrical model of the human eye is constructed from available measurements and determination of physicochemical properties of the sclera and the choroid, such as their effective diffusivity D and porous medium permeability K. Position and time dependent concentrations of the drug in the sclera and the choroid are predicted and the relative magnitudes of the periocular, vitreous and circulation losses are compared for various blood flow velocities $U_{b}$ . The simulations also predict the transient mean plasma concentration $\bar{C}$ of the drug anecortave desacetate in the choroid and the effect of choroidal blood flow on the peak mean plasma concentration ${\bar{C}}_{\max}$ . Comparison of predicted $\bar{C}$ with available experimental results is good.
Vision and the hypothalamus
2010, Optometry
Citation 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.
For nearly 2 millennia, signs of hypothalamic-related vision disorders have been noticed as illustrated by paintings and drawings of that time of undiagnosed Horner's syndrome. It was not until the 1800s, however, that specific connections between the hypothalamus and the vision system were discovered. With a fuller elaboration of the autonomic nervous system in the early to mid 1900s, many more pathways were discovered. The more recently discovered retinohypothalamic tracts show the extent and influence of light stimulation on hypothalamic function and bodily processes. The hypothalamus maintains its myriad connections via neural pathways, such as with the pituitary and pineal glands; the chemical messengers of the peptides, cytokines, and neurotransmitters; and the nitric oxide mechanism. As a result of these connections, the hypothalamus has involvement in many degenerative diseases. A complete feedback mechanism between the eye and hypothalamus is established by the retinohypothalamic tracts and the ciliary nerves innervating the anterior pole of the eye and the retina. A discussion of hypothalamic-related vision disorders includes neurologic syndromes, the lacrimal system, the retina, and ocular inflammation. Tables and figures have been used to aid in the explanation of the many connections and chemicals controlled by the hypothalamus. The understanding of the functions of the hypothalamus will allow the clinician to gain better insight into the many pathologies associated between the vision system and the hypothalamus. In the future, it may be possible that some ocular disease treatments will be via direct action on hypothalamic function.
Introduction
2007, Survey of Ophthalmology
Preclinical Efficacy of Anecortave Acetate
2007, Survey of Ophthalmology
Citation 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 Ophthalmology
Citation 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.
To develop a safe and effective transcleral delivery of anecortave acetate, a novel angiostatic cortisene, in therapeutic concentrations to the choroid and retina in the region of the macula in patients with age related macular degeneration.
In pre-clinical studies with rabbits and monkeys, several routes of delivery were studied including oral and other systemic routes as well as topical, subconjunctival, intravitreal injections and posterior juxtascleral administration. In addition, posterior juxtascleral depot administration using a specially designed blunt cannula was evaluated in humans.
Oral and other systemic routes were not acceptable due to rapid systemic metabolism. Topical and subconjunctival administrations resulted in subtherapeutic concentrations in the macular region (<0.1 μm). Intravitreal injections resulted in adequate drug levels, but the visual axis was obscured due to the opaque nature of the drug, and this method carries risks of endophthalmitis and retinal detachment. Posterior juxtascleral depot administration in rabbits and monkeys resulted in adequate retinal and choroidal drug levels (≥0.1 μm) up to 6 months after administration. In clinical studies, this administration technique was found to be safe.
Posterior juxtascleral depot administration of anecortave acetate onto the scleral surface near the macula is a safe and effective method for delivering therapeutic concentrations of drug to the macular region of the choroid and retina for up to 6 months.
Preclinical Safety of Anecortave Acetate
2007, Survey of Ophthalmology
Citation 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.
A number of preclinical safety pharmacology and toxicity studies have been performed on the angiostatic cortisene anecortave acetate in various species and using different routes of administration (oral, intravenous, subcutaneous, topical ocular, intraocular injection, posterior juxtascleral) and a wide range of doses (0–1,000 mg/kg). Anecortave acetate did not interact with a broad panel of pharmacological receptors and had no apparent pharmacological effects on major organ systems including the central nervous, gastrointestinal, renal, cardiovascular, and respiratory systems. Oral, topical ocular, and posterior juxtascleral administration of anecortave acetate had no significant ocular or systemic side effects or toxicity. In addition, there was no significant carcinogenic or reproductive/developmental toxicity associated with anecortave acetate in genotoxicity, carcinogenicity, and reproductive toxicity studies.

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: The authors are employees of Alcon Research, Ltd., Fort Worth, TX.

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Pharmacokinetics and Metabolism of Anecortave Acetate in Animals and Humans

Abstract

Section snippets

Pharmacokinetics in Animals

Pharmacokinetics in AMD Patients

Metabolism of Anecortave Acetate

In Vitro Protein Binding

Age/Elderly

Gender

Discussion

Am J Ophthalmol

Surv Ophthalmol

Am J Ophthalmol

Surv Ophthalmol

Ophthalmology

AL-3789: a novel ophthalmic angiostatic steroid

Expert Opin Investig Drugs

Anecortave acetate as monotherapy for treatment of subfoveal neovascularization in age-related macular degeneration: twelve-month clinical outcomes

Ophthalmology

Anecortave acetate as monotherapy for the treatment of subfoveal lesions in patients with exudative age-related macular degeneration (AMD): interim (month 6) analysis of clinical safety and efficacy

Retina