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Durezol (Difluprednate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

DUREZOL (difluprednate ophthalmic emulsion) 0.05% is a sterile, topical anti-inflammatory corticosteroid for ophthalmic use. The chemical name is 6α,9difluoro-11β,17,21-trihydroxypregna-1,4-diene-3,20-dione 21-acetate 17-butyrate (CAS number 23674-86-4). Difluprednate is represented by the following structural formula:

Difluprednate has a molecular weight of 508.56, and the empirical formula is C27H34F2O7.

Each mL contains: ACTIVE: difluprednate 0.5 mg (0.05%); INACTIVE: boric acid, castor oil, glycerin, polysorbate 80, water for injection, sodium acetate, sodium EDTA, sodium hydroxide (to adjust the pH to 5.2 to 5.8). The emulsion is essentially isotonic with a tonicity of 304 to 411 mOsm/kg. PRESERVATIVE: sorbic acid 0.1%.

CLINICAL PHARMACOLOGY

Mechanism of Action

Corticosteroids inhibit the inflammatory response to a variety of inciting agents and may delay or slow healing. They inhibit edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotreines by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.

Difluprednate is structurally similar to other corticosteroids.

Pharmacokinetics

Difluprednate undergoes deacetylation in vivo to 6α, 9-difluoroprednisolone 17-butyrate (DFB), an active metabolite of difluprednate.

Clinical pharmacokinetic studies of difluprednate after repeat ocular instillation of 2 drops of difluprednate (0.01% or 0.05%) four times per day for 7 days showed that DFB levels in blood were below the quantification limit (50 ng/mL) at all time points for all subjects, indicating the systemic absorption of difluprednate after ocular instillation of DUREZOL is limited.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Difluprednate was not genotoxic in vitro in the Ames test, and in cultured mammalian cells CHL/IU (a fibroblastic cell line derived from the lungs of newborn female Chinese hamsters). An in vivo micronucleus test of difluprednate in mice was also negative. Treatment of male and female rats with subcutaneous difluprednate up to 10 mcg/kg/day prior to and during mating did not impair fertility in either gender. Long term studies have not been conducted to evaluate the carcinogenic potential of difluprednate.

Animal Toxicology and/or Pharmacology

In multiple studies performed in rodents and non-rodents, subchronic and chronic toxicity tests of difluprednate showed systemic effects such as suppression of body weight gain; a decrease in lymphocyte count; atrophy of the lymphatic glands and adrenal gland; and for local effects, thinning of the skin; all of which were due to the pharmacologic action of the molecule and are well known glucocorticosteroid effects. Most, if not all of these effects were reversible after drug withdrawal. The NOEL for the subchronic and chronic toxicity tests were consistent between species and ranged from 1-1.25 mcg/kg/day.

CLINICAL STUDIES

Ocular Surgery

Clinical efficacy was evaluated in 2 randomized, double-masked, placebo-controlled trials in which subjects with an anterior chamber cell grade ≥ "2" (a cell count of 11 or higher) after cataract surgery were assigned to DUREZOL or placebo (vehicle) following surgery. One drop of DUREZOL or vehicle was self instilled either 2 times per day or 4 times per day for 14 days, beginning the day after surgery. The presence of complete clearing (a cell count of 0) was assessed 8 and 15 days post-surgery using a slit lamp binocular microscope. In the intent-to-treat analyses of both studies, a significant benefit was seen in the 4 times per day DUREZOL-treated group in ocular inflammation and reduction of pain when compared with placebo. The consolidated clinical trial results are provided below.

Ocular Inflammation and Pain Endpoints (Studies Pooled)
DUREZOL
4 times per day 
N = 107
Vehicle
N = 220
Day 8 15 8 15
Anterior Chamber cell clearing (% subjects) 24
(22%) 1
44
(41%)
17
(7%)
25
(11%)
Pain free (% subjects) 62
(58%)
67
(63%)
59
(27%)
76
(35%)

1 Statistically significantly better than vehicle, P<0.01

Endogenous Anterior Uveitis

Clinical efficacy was evaluated in two randomized, double masked active controlled trials in which patients who presented with endogenous anterior uveitis were treated with either DUREZOL 4 times daily or prednisolone acetate ophthalmic suspension, 1%, 8 times daily for 14 days.  Both studies demonstrated that DUREZOL was equally effective as prednisolone acetate ophthalmic suspension, 1% in treating subjects with endogenous anterior uveitis. 

Mean Change from Baseline in Anterior Chamber Cell Grade 1
Study 1
time point
DUREZOL
N=57
Prednisolone Acetate
N=53
Difference 2
(95% CI)
Baseline 2.6 2.5  0.0  (-0.22, 0.28) 
Day 3 -1.0 -1.0 -0.1  (-0.35, 0.25)
Day 7 -1.6 -1.5 -0.0  (-0.31, 0.25)
Day 14 -2.0 -1.8 -0.2  (-0.46, 0.10)
Day 21 -2.2 -1.9 -0.3  (-0.53, 0.01)
Day 28 -2.2 -2.1 -0.1  (-0.37, 0.18)
Day 35 -2.1 -2.0 -0.1  (-0.39, 0.20)
Day 42 -2.1 -2.1  0.0  (-0.27, 0.34)
Study 2
time point
DUREZOL
N=50
Prednisolone Acetate
N=40
Difference
(95% Cl)
Baseline 2.4 2.4 0.0  (-0.21, 0.29)
Day 3 -0.9 -0.9 -0.0  (-0.34, 0.25)
Day 7 -1.7 -1.6 -0.1  (-0.35, 0.21)
Day 14 -1.9 -1.8 -0.1  (-0.34, 0.20)
Day 21 -2.0 -2.0 0.0  (-0.25, 0.28)
Day 28 -2.0 -2.0 0.0  (-0.21, 0.26)
Day 35 -2.1 -2.0 -0.1  (-0.32, 0.16)
Day 42 -2.0 -1.9 -0.1  (-0.36, 0.24)

1 with 5 grades: 0 = 0 cells; 1 = 1 to 10 cells; 2 = 11 to 20 cells; 3 = 21 to 50 cells; and 4 = >50 cells
2 adjusted for baseline AC cell grade and study center and based on ITT dataset with LOCF for missing data

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