Clobex Spray - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Clobex Spray - Scientific Information

Manufacture: Galderma Laboratories
Country: Canada
Condition: Psoriasis vulgaris (Plaque Psoriasis), Psoriasis
Class: Topical steroids
Form: Spray
Ingredients: Clobetasol propionate, alcohol, isopropyl myristate, isopropyl myristate, undecylenic acid

Pharmaceutical Information

Drug Substance

Proper name: Clobetasol propionate
Chemical name:

21-chloro-9-fluoro-11∃, 17-dihydroxy-16∃ -methylpregna-1, 4-diene-3, 20-dione 17-propionate

Molecular formula: C25H32ClFO5 (CAS Registry Number 25122-46-7)
Molecular mass: 466.97 grams/mole
Structural formula:



Physicochemical properties: White to practically white crystalline powder that is insoluble in water, and has a melting point of approximately 196ºC.

Clinical Trials

Study Demographics and Trial Design

Table 1 Summary of patient demographics for clinical trials in moderate to severe plaque psoriasis
Study # Trial design Dosage, route of administration and duration Study subjects
(n=number)
Mean age
(Range)
Gender
TI01-01008 Multicentre, randomized, double-blind, vehicle-controlled, parallel comparison Twice daily application of a thin film to psoriatic plaques for up to four weeks 120 (60/arm) 48
(21-76)
72 M / 48 F
TI01-01010 Multicentre, randomized, double-blind, vehicle-controlled, parallel comparison Twice daily application of a thin film to psoriatic plaques for up to four weeks 120 (60/arm) 46
(18-81)
36 M / 29 F

Two multicentre, randomized, blinded, vehicle controlled studies were performed in patients with moderate to severe plaque psoriasis covering at least 2% of the body surface area. Patients were treated twice daily for up to four weeks with either Clobex Spray (clobetasol propionate solution) 0.05% or Spray Vehicle.

Study Results

Efficacy assessments were based on Investigator assessments of the signs and symptoms of psoriasis. The primary measure of efficacy variable was the Overall Disease Severity score, dichotomized to success or failure. Success was defined as a Grade of 2 or less on a 0-4 point scale at Week 2 or earlier and defined as a Grade of 1 or less on a 0-4 point scale at the end of treatment (Week 4 or later).

Table 2 Results of Studies TI01-01008 and TI01-01010, separately and combined, in moderate to severe plaque psoriasis
Study No. Primary Endpoint Clobex Spray, 0.05% Spray Vehicle Statistical Significancec
TI01-01008 Week 2 Overall Disease Severitya
Success
Failure

Week 4 Overall Disease Severityb
Success
Failure
87%
13%


78%
22%
28%
72%


3%
97%
p < 0.001



p < 0.001
TI01-01010 Week 2 Overall Disease Severitya
Success
Failure

Week 4 Overall Disease Severityb
Success
Failure
87%
13%


82%
18%
27%
73%


2%
98%
p < 0.001




p < 0.001
Combined Week 2 Overall Disease Severitya
Success
Failure

Week 4 Overall Disease Severityb
Success
Failure
87%
13%


80%
20%
28%
72%


3%
97%
p < 0.001



p < 0.001

a Success is defined as a grade of 2 or less on the 0-4 point Overall Disease Severity Scale.

b Success is defined as a grade of 1 or less on the 0-4 point Overall Disease Severity Scale.

c P-value from a Cochran-Mantel-Haenszel test, stratified by grouped study sites. The Week 4 analysis is considered statistically significant if and only if statistical significance is achieved for both the Week 2 and Week 4 analyses.

Detailed Pharmacology

Animal Studies

Pharmacodynamics

In Vitro Studies

Although its mechanism of action has not been established, clobetasol propionate is thought to act by induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. In literature, among others by Schimmer and Parker6 it is described that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. The physiological release of arachidonic acid from membrane phospholipids is under control of phospholipase A2.

In Vivo Studies

Dermatopharmacologic investigations were reported by Yawalkar et al.10 on clobetasol propionate in comparison with two other topical corticosteroids (halobetasol propionate and hydrocortisone). Several animal models as the croton oil-induced ear edema model in rats and mice, and the ultraviolet-induced dermatitis inhibition test in guinea pigs demonstrated the effects of clobetasol propionate on topical non-immune inflammation. Again, Yawalkar et al.10 demonstrated the effects of clobetasol propionate in comparison with halobetasol propionate and hydrocortisone on topical immune inflammation, in oxazolone -induced dermatitis in rats and mice. Bäck and Egelrud1 utilised a picryl chloride contact sensitivity model, demonstrating that topical application of clobetasol propionate completely suppressed the hypersensitization reaction, resulting in total inhibition of the inflammatory oedema. The inflammation was reduced to a great extent in the control ear not treated with clobetasol propionate, indicating a systemic effect of the product.

The fact that clobetasol propionate could induce a six-fold induction of ethoxycoumarin-O- dealkylase activity in skin2 indicates that there is a potential for drug-drug interaction with other topical drugs that could be metabolised by the same enzyme.

Pharmacokinetics

The metabolism of clobetasol propionate has never been fully characterized or quantified; it is assumed that its metabolism follows that of systemically administered adrenocortical steroids. The metabolism of steroid hormones involves sequential addition of oxygen or hydrogen atoms followed by conjugation to form water-soluble derivatives. The double bond at the 4, 5 position is reduced both in the liver and extrahepatically to produce inactive compounds. Reduction of the 3-ketone group to a 3-hydroxyl group occurs only in the liver. Most of these reduced compounds are subsequently conjugated with glucuronide or sulfate in the liver, and to a lesser extent in the kidney. These sulfate esters and glucuronides form water-soluble derivatives that are excreted in the urine6.

In the animal species evaluated, the primary excretion route of clobetasol propionate after dermal dosing was via feces. The totals excreted via feces and urine up to the 96th hour after administration was 9.20%, 1.22% and 8.86% of the administered radioactivity for cream, ointment and solution, respectively. The remaining amounts in the body (excluding site of application) were 0.92%, 0.42% and 2.85% of the administered amount, respectively. These results indicated that when applied dermally, the absorption was satisfactory with the cream and solution but not with the ointment, and that when the drug was administered in the form of cream or solution (dermally), a reasonable plasma concentration of the drug could be maintained for a long period of time, even after a single administration.

Human Studies

Pharmacodynamics

In Vivo Studies

Results of a study in healthy volunteers have shown the vasoconstrictive capacity of Clobex Spray (clobetasol propionate solution) 0.05% to be comparable to that of a cream formulation of clobetasol propionate 0.05% and superior to that of amcinonide 0.1% cream.

Pharmacokinetics

There are no human data regarding the distribution of corticosteroids to body organs following topical application. Nevertheless, once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids absorbed through the skin are metabolized primarily in the liver and are then excreted by the kidneys. In addition, some corticosteroids and their metabolites are also excreted in the bile.

If absorbed through the skin, clobetasol propionate will be metabolised by the liver and excreted primarily via bile into the feces.

Toxicology

Human Studies

A 21-day cumulative irritation test was performed to assess the potential of the test product, Clobex Spray (clobetasol propionate solution), 0.05%, and Spray Vehicle to induce dermal irritation as a result of repeated applications. Each subject received up to a total of 18 applications each of Clobex Spray, 0.05%, Spray Vehicle, and the positive control 0.5% Sodium Lauryl Sulfate solution under occlusive patches over a three week period. Patches containing test material were placed on the backs of subjects and left in place for 24 hours. After a minimum of five minutes from patch removal, the sites were graded for irritation. Based on the cumulative irritation scores recorded, Clobex Spray, 0.05%, and Spray Vehicle were classified as somewhat irritating, while the positive control was classified as extremely irritating.

A repeated insult patch test was conducted to assess the potential of Clobex Spray, 0.05% and Spray Vehicle to induce dermal irritation and contact allergy as a result of repeated applications. This study consisted of three phases; I) a three week induction phase, ii) a two week rest period, and iii) a challenge phase. During the three week induction phase, test materials were applied three times per week (Monday, Wednesday, and Friday). After a two week rest period, one challenge application of each test material was made. Each subject received a total of ten applications of each test article over a six-week period.

During the induction phase the majority of reactions were rated as no sign of irritation, slight erythema or noticeable erythema with slight irritation. During the challenge phase, the both test articles typically produced slight erythema, and Clobex Spray, 0.05% and the Spray Vehicle were considered by the investigator to be somewhat irritating and not sensitizers.

A phototoxicity study was performed to assess the phototoxicity potential of Clobex Spray, 0.05% and of the Spray Vehicle following exposure to UVA and UVB light. There was one Grade 1 reaction at the 48 hour post irradiation grading at sites for each of the test articles. All other grades at irradiated sites were zeroes. The scores for all non-irradiated sites and the irradiated control site were also all zeroes. Both the Clobex Spray, 0.05% and the Spray Vehicle were considered by the investigator to be "not phototoxic.”

A photocontact allergy study was performed to assess the safety and photocontact allergy potential of, Clobex Spray, 0.05% and the Spray Vehicle. During the induction phase, all of the reactions at irradiated sites were rated as no sign of irritation, slight erythema, or noticeable erythema with slight irritation for both Clobex Spray, 0.05% and for the Spray Vehicle. At non-irradiated sites the majority of reactions were no sign of irritation or very slight erythema, with only few graded as noticeable erythema with slight irritation for both products.

During the challenge phase, three subjects treated with Clobex Spray, 0.05% had slight erythema that fell to no sign of irritation at the final assessment of the irradiated sites. In the Spray Vehicle group, four subjects had a reaction graded as slight erythema at the final grading and five subjects had either slight erythema or noticeable erythema with irritation that fell to no sign of irritation at the final grading. Both Clobex Spray, 0.05% and the Spray Vehicle were considered not to cause photoallergy reactions by the investigator.

Animal Studies

Acute Toxicity

Acute toxicity was determined in mice and rats using subcutaneous, oral, and intraperitoneal routes. The animals received a single dose of different concentrations of clobetasol propionate and were observed for three consecutive weeks. The LD50 value obtained by the subcutaneous route in mice was 81.7 mg/kg for all animals. None of the mice died after oral administration up to 3 g/kg. The LD50 value obtained by the intraperitoneal route in mice was 156 mg/kg for males and 118 mg/kg for females. The subcutaneous LD50 value for male rats was 397 mg/kg and 366 mg/kg for female rats. None of the rats died after oral administration up to 3 g/kg. The LD50 value by the intraperitoneal route for male rats was 414 mg/kg and 351 mg/kg for females rats. (Kuramoto 1975)

Repeated Dose Toxicity

Using Clobex Spray, 0.05%, a no observed effect dose level (NOEL) of 150 mg formulation/kg/day (safety factor of 0.9) was established for systemic toxicity in a 90-day subchronic micropig study. In a dermal toxicity study with Hanford minipigs, doses of 60, 120 and 240 mg/kg/day (safety factor 0.3, 0.65, 1.3, respectively) of Clobex Spray, 0.05%, were applied for nine months followed by a one month recovery. Treatment related decreases in body weight and histopathological findings precluded the determination of a NOEL in this study.

A 90-day dermal irritation study was conducted in Sprague Dawley rats. Concentration of clobetasol propionate was varied to produce 0.001%, 0.005%, 0.015%, and 0.05% sprays. Dosing was rotated between two 20 cm2 sites on the back and a constant volume of 0.16 mL/kg/dose (800 mg formulation/m2/dose) was chosen based on the results a vehicle dose range finding study that found 0.24 mL/kg/dose could be tolerated in rats for 14 days. Based on the results of this study, the no-observed-adverse-effect (NOAEL) level was considered to be the 0.001% or 0.13 mg/kg (safety factor of 0.007). The effects noted during or at the end of the treatment period were reversible and most resolved almost completely by the end of a one month recovery period.

Carcinogenicity

Few animal studies have been performed to evaluate the carcinogenic potential of isopropyl myristate and there are no detailed systemic absorption data for this compound in humans or animals.

No classical animal studies have been performed to evaluate the carcinogenic potential of clobetasol propionate.

One 18-month study was performed in mice to evaluate the carcinogenic potential of fluticasone propionate (medium-potency corticosteroid) when given topically as a 0.05% ointment. No evidence of carcinogenicity was found in this study. No evidence of pre-neoplastic lesions was noted in a 6-month toxicity study performed with clobetasol propionate by the subcutaneous route in rats.

Mutagenicity

Clobetasol propionate was negative in the in vivo mammalian erythrocyte micronucleus test and in the in vitro mammalian chromosome aberration test conducted.

Reproductive Toxicity

Segment I fertility studies in rats following oral administration at doses up to 50 Φg/kg per day revealed an increase in the number of the resorbed embryos and a decrease in the number of living foetuses at the highest dose.

In another Segment I study, male rats were dosed subcutaneously twice daily beginning 70 days before cohabitation and continuing through the day before sacrifice and female rats were dosed twice daily beginning 15 days before cohabitation and continuing through Day 7 of presumed gestation. A dosage

level of less than 12.5Φg/kg/day clobetasol propionate (safety factor 0.03) was considered to be the NOEL for paternal and maternal general toxicity and male reproductive toxicity. The female reproductive NOEL was 12.5 Φg/kg/day (safety factor 0.03).

Segment II teratogenicity studies in mice, rats and rabbits showed clobetasol propionate to be teratogenic when administered sub-cutaneously or topically. Abnormalities seen include fetal immaturity and several malformations, cleft palate, cranioschisis and skeletal abnormalities, in combination with maternal toxicity. There are no adequate and well-controlled studies in pregnant women.

A Segment II study was performed in rats using Clobetasol Propionate Lotion applied dermally at dose levels of 0.05, 0.15, and 0.5 mg/kg/day. Dose-related maternal and fetal toxicity was observed, and fetal immaturity was observed at all dose levels. A variety of fetal malformations were observed at 0.15 and 0.5 mg/kg/day, in combination with maternal toxicity.

In a Segment III study, females were dosed with clobetasol propionate suspended in 0.04% Tween 80 in saline administered subcutaneously from Day 7 of presumed gestation through Day 20 postpartum or Day 24 presumed gestation for those rats that did not deliver a litter. The maternal NOEL for clobetasol propionate was less than 12.5 g/kg/day (safety factor 0.03) due to reduced body weight gain and feed consumption during the gestation period. The reproductive NOEL in the dams was 25 g/kg/day (safety factor 0.07). The NOAEL for viability and growth in the offspring was 12.5 g/kg/day (safety factor 0.03).

Local Tolerance

Results from special toxicity studies evaluating primary dermal and ocular irritation potential showed that Clobex Spray, 0.05% is not a skin irritant or a skin sensitizer, but does produce moderate irritation in the Kay and Calandra Ocular Evaluation.