A Phase 1 Study to Investigate the Effects of Cortexolone 17α-Propionate, Also Known as Clascoterone, on the QT Interval Using the Meal Effect to Demonstrate ECG Assay Sensitivity.

Cortexolone 17α-propionate, also known as clascoterone, is a potent androgen receptor inhibitor intended for the topical treatment of skin diseases associated with androgenic pathway alterations. In nonclinical studies, cortexolone 17α-propionate was found to have a weak inhibitory effect on human Ether-à-go-go-Related Gene (hERG) potassium channels, which are vital for normal electrical activity in the heart. When used in a cream formulation, little cortexolone 17α-propionate is absorbed. However, the solution formulation developed for the treatment of androgenetic alopecia leads to a measurable systemic concentration and accumulation of the antiandrogen. This phase 1 study assessed the effect of cortexolone 17α-propionate on the QTc interval using concentration-effect analysis and the effect of a meal on QTc to confirm assay sensitivity. Thirty-two volunteers were randomly assigned to receive the active drug or a matching vehicle as placebo. Participants were dosed twice daily on days 1 to 3 (225 mg applied topically as a 7.5% solution 12 hours apart) and once on day 4. Pharmacokinetic and electrocardiogram assessments were performed after supratherapeutic doses. Assay sensitivity was successfully confirmed by using the food effect on the QTc interval. The results of this concentration-QTc analysis demonstrate that cortexolone 17α-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested.

Clascoterone: First Approval.

Clascoterone (Winlevi®) is an androgen receptor inhibitor being developed as a topical cream and solution by Cassiopea (a spin-out company of Cosmo Pharmaceuticals) for the treatment of androgen-dependent skin disorders, including androgenetic alopecia and acne vulgaris. Although the exact mechanism of action of clascoterone for the topical treatment of acne vulgaris is unknown, the drug is believed to compete with the androgen dihydrotestosterone for binding to androgen receptors in the sebaceous gland and hair follicles to attenuate signalling necessary for acne pathogenesis. In August 2020, clascoterone cream 1% received its first approval in the USA for the topical treatment of acne vulgaris in patients 12 years of age or older. Clinical studies of a different formulation of clascoterone (a solution containing a higher concentration of the drug) for the treatment of androgenetic alopecia are underway in Germany and the USA. This article summarizes the milestones in the development of clascoterone leading to this first approval for the topical treatment of acne vulgaris.

Pharmacokinetic Profile, Safety, and Tolerability of Clascoterone (Cortexolone 17-alpha propionate, CB-03-01) Topical Cream, 1% in Subjects With Acne Vulgaris: An Open-Label Phase 2a Study

Clascoterone (cortexolone 17α-propionate, CB-03-01) 1% cream, a topical, androgen receptor (AR) inhibitor under investigation for the treatment of acne vulgaris, is rapidly metabolized to cortexolone in human plasma. The primary objectives of this study were to determine the pharmacokinetic (PK) properties and adrenal suppression potential of clascoterone topical cream, 1% in subjects with acne vulgaris. Study Design: This study was an open-label, multicenter study in 42 subjects ≥12 years of age with moderate-to-severe acne (Grade 3-4 on the Investigator's Global Assessment [IGA]), on the face, chest and/or back. Cohort 1(>18 years of age) and Cohort 2 (12-18 years of age) applied clascoterone topical cream, 1% twice daily (BID) for 14 days. Primary safety endpoints included hypothalamic-pituitary-adrenal (HPA) axis response to cosyntropin via a Cosyntropin Stimulation Test (CST) upon screening (day 1) and at day 14 (HPA axis suppression was defined as a post-stimulation serum cortisol level <18 µg/dL at day 14); and PK evaluation including concentration-time profiles of clascoterone and cortexolone in plasma­PK parameters were determined using "non-compartmental" analysis. Secondary safety endpoints included clinical laboratory testing, local and systemic adverse events (AEs), physical examination/vital signs, and electrocardiogram (ECG). Results: 42 subjects (Cohort 1=20, Cohort 2= 22) enrolled. Cohort 1 was comprised of 15 females (15/20, 75%) and 5 males (5/20, 25%), non-Hispanic/Latino (20/20, 100%), mean age is 24.4 years. Cohort 2 was comprised of 12 females (12/22, 54.5%) and 10 males (10/22, 45.5%), non-Hispanic/Latino (21/22, 95.5%), and mean age is 15.6 years. Three subjects (3/42,7%), 1 adult and 2 adolescents, demonstrated an abnormal HPA axis response with post-stimulation serum cortisol levels ranging from 14.9 to 17.7 µg/dL at day 14. All returned to normal HPA axis function, four weeks after day 14. None showed clinical evidence of adrenal suppression. Clascoterone plasma concentrations achieved PK steady-state by day 5. Clascoterone systemic exposure was similar between both cohorts. At steady-state, plasma concentrations increased ~1.8 to 2.1 fold versus first dose with mean (coefficient of variation [CV] %) maximum plasma concentrations of 4.4 ng/mL (67%) and 4.6 ng/mL (103%) in Cohort 1 and Cohort 2, respectively. Cortexolone plasma concentrations trended below the lower limit of quantitation (0.5 ng/mL) in both cohorts. Local skin reactions (LSRs) were mostly mild, with only one moderate case of pruritus. There were nine AEs categorized as follows: definitely related (N=2), probably related (N=4), unlikely/not related (N=3), to clascoterone. Conclusion: This study demonstrates the safety and tolerability of clascoterone topical cream, 1% in adolescents and adults with acne vulgaris treated BID for 14 consecutive days. J Drugs Dermatol. 2019;18(6):563-568.

Comparison of triamcinolone acetonide, 11-deoxycortisol and other lipid formulae for the visualization of vitreous body in the anterior chamber after posterior capsule rupture in animal models.

PURPOSE: The efficacy and toxicity of triamcinolone acetonide and other lipid formulae--calcium palmitate, cholesterol and 11-deoxycortisol--in the visualization of the prolapsed vitreous body in the anterior chamber after posterior capsule rupture were investigated in animal models. METHODS: In porcine eyes, a suspension of calcium palmitate, cholesterol, triamcinolone acetonide and 11-deoxycortisol was injected into the anterior chamber after intentionally creating posterior capsule rupture. Following gentle irrigation and aspiration, the vitreous body prolapsed in the anterior chamber was removed using an anterior vitrectomy cutter. In phakic rabbit eyes, the side-effects of the reagents were assessed for biomicroscopic appearance, intraocular pressure (IOP) and corneal histology. RESULTS: The suspension of calcium palmitate, cholesterol, triamcinolone acetonide and 11-deoxycortisol was effective in the visualization of the vitreous body prolapsed in the anterior chamber after posterior capsule rupture. When cholesterol and calcium palmitate were injected into the anterior chamber, they remained there; this induced a significant increase in IOP and corneal oedema. In contrast, most of the triamcinolone acetonide and 11-deoxycortisol that was injected into the anterior chamber had disappeared a day after the injection without affecting IOP or corneal endothelial density. When injected into the intravitreous cavity, triamcinolone led to a significant increase in IOP 2 and 4 weeks after the injection. However, calcium palmitate, cholesterol and 11-deoxycortisol injected into the vitreous cavity had no effect on IOP at 4 weeks. CONCLUSION: The suspension of triamcinolone acetonide and 11-deoxycortisol was effective in visualizing the vitreous body prolapsed in the anterior chamber after posterior capsule rupture. However, the amount of the reagent must be kept to a minimum to prevent the potential risk of ocular toxicities and postoperative late-onset ocular hypertension.

Use of steroid profiles in determining the cause of adrenal insufficiency.

HYPOTHESIS: A cortisol response to adrenocorticotropin injection is the standard test for diagnosing adrenal insufficiency. Multiple steroid hormones can now be accurately measured by tandem mass spectrometry in a single sample. The study objective was to determine whether a steroid profile, created by simultaneous measurement of 10 steroid hormones by tandem mass spectrometry, would help determine the cause of adrenal insufficiency. DESIGN: A 10-steroid profile was measured by tandem mass spectrometry during the performance of a standard high dose cortrosyn stimulation test. The steroids were measured at baseline, 30, and 60min following synthetic adrenocorticotropin injection. Adrenal insufficiency was defined as a peak cortisol level of less than 20microg/dL. Testing was conducted in the general clinical research center of a university medical center. Normal volunteers, patients suspected of having adrenal insufficiency, and patients with known adrenal insufficiency participated. RESULTS: Our results showed that adrenal insufficiency of any cause was adequately diagnosed using the response of 11-deoxycortisol, dehydroepiandrosterone, or these analytes combined in a two-steroid profile. A three-steroid profile yielded a test with 100% accuracy for discriminating primary adrenal insufficiency from normal status. Primary adrenal insufficiency was well separated from secondary adrenal insufficiency using only a single aldosterone value. 11-Deoxycortisol, dehydroepiandrosterone, and a two-steroid profile each provided fair discrimination between secondary adrenal insufficiency and normal status. CONCLUSIONS: We conclude that stimulated levels of aldosterone, 11-deoxycortisol, dehydroepiandrosterone, and a two- or three-steroid profile provided additional discrimination between states of adrenal sufficiency and insufficiency. It is proposed that a steroid profile measuring cortisol, aldosterone, 11-deoxycortisol, and dehydroepiandrosterone would potentially improve the ability to determine the cause of adrenal insufficiency.

The effect of the corticosteroid hormone cortexolone on the metabolites produced during phenanthrene biotransformation in Cunninghamella elegans.

The metabolism of phenanthrene and the mammalian corticosteroid hormone cortexolone by the fungus Cunninghamella elegans was studied. The amounts of the cortexolone transformation products, cortisol and epicortisol, were affected by the presence of phenanthrene. Approximately 40% more cortisol was produced by C. elegans in cultures with phenanthrene. In contrast, epicortisol formation decreased. C. elegans transformed phenanthrene to phenanthrene trans-1,2-,3,4-, and 9,10-dihydrodiols, phenols, diphenols (diols) and glucoside conjugates of 1-, 2-, 3-, 4-, and 9-phenanthrols. Almost all of the phenanthrene initially added was metabolized to ethyl acetate extractable metabolites. In the mycelia and culture medium extracts, phenanthrol glucosides represented 80% and 94% of the total metabolites, respectively. The major metabolite was the glucoside conjugate of 1-phenanthrol. The presence of cortexolone affected the biodegradation of phenanthrene by decreasing the amounts of phenanthrene metabolites compared to control cultures.

Visualizing the vitreous body in the anterior chamber using 11-deoxycortisol after posterior capsule rupture in an animal model.

OBJECTIVE: To develop a new technique to visualize vitreous body prolapsed in the anterior chamber using 11-deoxycortisol. STUDY DESIGN: Experimental study. METHODS: An animal model of posterior capsule rupture was developed to investigate the usefulness of 11-deoxycortisol, a precursor of cortisol without steroid activity. After the intentional creation of posterior capsule rupture, the suspension of 11-deoxycortisol was injected into the anterior chamber of rabbit eyes. After gentle irrigation and aspiration, the vitreous body that had prolapsed into the anterior chamber was removed using an anterior vitrectomy cutter. To investigate the safety of 11-deoxycortisol, the biomicroscopic appearance, intraocular pressure (IOP), corneal endothelial count, and microstructure of the corneal endothelium were examined in the rabbits that received injections of 11-deoxycortisol in the anterior chamber. RESULTS: In our posterior capsule rupture model, the vitreous in the anterior chamber became clearly visible, with 11-deoxycortisol showing white particles entrapped on its surface. The injection of 11-deoxycortisol facilitated the complete removal of the vitreous body from the anterior chamber. In intact rabbit eyes, most of the injected 11-deoxycortisol had disappeared from the anterior chamber by 12 hours after injection. The injection of 11-deoxycortisol had no effect on IOP, corneal endothelial density, or the microstructure of the corneal endothelium. CONCLUSIONS: The injection of 11-deoxycortisol in the anterior chamber is useful in visualizing the vitreous body and has no significant side effects. This technique might reduce the intraoperative and postoperative complications of anterior vitrectomy after posterior capsule rupture.