Clobetasol (Clobetasol Propionate Topical) - Description and Clinical Pharmacology

DESCRIPTION

The active component of FLOVENT DISKUS is fluticasone propionate, a corticosteroid having the chemical name S -(fluoromethyl) 6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate and the following chemical structure:

Fluticasone propionate is a white powder with a molecular weight of 500.6, and the empirical formula is C₂₅H₃₁F₃O₅S. It is practically insoluble in water, freely soluble in dimethyl sulfoxide and dimethylformamide, and slightly soluble in methanol and 95% ethanol.

FLOVENT DISKUS is a specially designed plastic inhalation delivery system containing a double-foil blister strip of a powder formulation of fluticasone propionate intended for oral inhalation only. The DISKUS^® inhalation unit, which is the delivery component, is an integral part of the drug product. Each blister on the double-foil strip within the unit contains 50 mcg of microfine fluticasone propionate in 12.5 mg of formulation containing lactose (which contains milk proteins). After a blister containing medication is opened by activating the DISKUS, the medication is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, FLOVENT DISKUS 50 mcg delivers 46 mcg of fluticasone propionate when tested at a flow rate of 60 L/min for 2 seconds. In adult patients with obstructive lung disease and severely compromised lung function (mean forced expiratory volume in 1 second [FEV₁] 20% to 30% of predicted), mean peak inspiratory flow (PIF) through a DISKUS^® was 82.4 L/min (range, 46.1 to 115.3 L/min). In children with asthma 4 and 8 years old, mean PIF through FLOVENT DISKUS was 70 and 104 L/min, respectively (range, 48 to 123 L/min).

The actual amount of drug delivered to the lung may depend on patient factors, such as inspiratory flow profile.

CLINICAL PHARMACOLOGY

Mechanism of Action

Fluticasone propionate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human corticosteroid receptor agonist with an affinity 18 times greater than dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown.

Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma.

Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer.

Studies in patients with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone propionate. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (<1%), and the minimal pharmacological activity of the only metabolite detected in man.

Pharmacokinetics

Absorption

Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed. The systemic bioavailability of fluticasone propionate from the DISKUS device in healthy volunteers averages 18%.

Peak steady-state fluticasone propionate plasma concentrations in adult patients with asthma (N = 11) ranged from undetectable to 266 pg/mL after a 500-mcg twice-daily dosage of fluticasone propionate inhalation powder using the DISKUS device. The mean fluticasone propionate plasma concentration was 110 pg/mL.

Distribution

Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg.

The percentage of fluticasone propionate bound to human plasma proteins averages 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.

Metabolism

The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17β-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the corticosteroid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

Elimination

Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.

Special Populations

Hepatic Impairment

Since fluticasone propionate is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of fluticasone propionate in plasma. Therefore, patients with hepatic disease should be closely monitored.

Gender

Full pharmacokinetic profiles were obtained from 9 female and 16 male patients given 500 mcg twice daily. No overall differences in fluticasone propionate pharmacokinetics were observed.

Pediatrics

In a clinical study conducted in patients 4 to 11 years of age with mild to moderate asthma, fluticasone propionate concentrations were obtained in 61 patients at 20 and 40 minutes after dosing with 50 and 100 mcg twice daily of fluticasone propionate inhalation powder using the DISKUS. Plasma concentrations were low and ranged from undetectable (about 80% of the plasma samples) to 88 pg/mL. Mean peak fluticasone propionate plasma concentrations at the 50- and 100-mcg dose levels were 5 and 8 pg/mL, respectively.

Other

Formal pharmacokinetic studies using fluticasone propionate have not been conducted in other special populations.

Drug Interactions

Fluticasone propionate is a substrate of cytochrome P450 3A4. Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (C_max) averaged 11.9 pg/mL (range, 10.8 to 14.1 pg/mL) and AUC_(0-τ) averaged 8.43 pg•hr/mL (range, 4.2 to 18.8 pg•hr/mL). Fluticasone propionate C_max and AUC_(0-τ) increased to 318 pg/mL (range, 110 to 648 pg/mL) and 3,102.6 pg•hr/mL (range, 1,207.1 to 5,662.0 pg•hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate concentration resulted in a significant decrease (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC).

Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are coadministered with fluticasone propionate. In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased plasma fluticasone propionate concentration and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol.

In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

Pharmacodynamics

In clinical trials with fluticasone propionate inhalation powder using dosages up to and including 250 mcg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol <18 mcg/dL assessed by radioimmunoassay) were noted both in patients receiving fluticasone propionate and in patients receiving placebo. The incidence of abnormal tests at 500 mcg twice daily was greater than placebo. In a 2-year study carried out with the DISKHALER® inhalation device in 64 patients with mild, persistent asthma (mean FEV₁ 91% of predicted) randomized to fluticasone propionate 500 mcg twice daily or placebo, no patient receiving fluticasone propionate had an abnormal response to 6-hour cosyntropin infusion (peak serum cortisol<18 mcg/dL). With a peak cortisol threshold <35 mcg/dL, 1 patient receiving fluticasone propionate (4%) had an abnormal response at 1 year; repeat testing at 18 months and 2 years was normal. Another patient receiving fluticasone propionate (5%) had an abnormal response at 2 years. No patient on placebo had an abnormal response at 1 or 2 years.

In a placebo-controlled clinical study conducted in patients 4 to 11 years of age, a 30-minute cosyntropin stimulation test was performed in 41 patients after 12 weeks of dosing with 50 or 100 mcg twice daily of fluticasone propionate via the DISKUS device. One patient receiving fluticasone propionate via DISKUS had a prestimulation plasma cortisol concentration <5 mcg/dL, and 2 patients had a rise in cortisol of <7 mcg/dL. However, all poststimulation values were >18 mcg/dL.

The potential systemic effects of inhaled fluticasone propionate on the hypothalamic-pituitary­adrenal (HPA) axis were also studied in patients with asthma. Fluticasone propionate given by inhalation aerosol at dosages of 220, 440, 660, or 880 mcg twice daily was compared with placebo or oral prednisone 10 mg given once daily for 4 weeks. For most patients, the ability to increase cortisol production in response to stress, as assessed by 6-hour cosyntropin stimulation, remained intact with inhaled fluticasone propionate treatment. No patient had an abnormal response (peak serum cortisol <18 mcg/dL) after dosing with placebo or fluticasone propionate 220 mcg twice daily. For patients treated with 440, 660, and 880 mcg twice daily, 10%, 16%, and 12%, respectively, had an abnormal response as compared to 29% of patients treated with prednisone.

To confirm that systemic absorption does not play a role in the clinical response to inhaled fluticasone propionate, a double-blind clinical study comparing inhaled fluticasone propionate powder and oral fluticasone propionate was conducted. Inhaled fluticasone propionate powder in dosages of 100 and 500 mcg twice daily was compared to oral fluticasone propionate 20,000 mcg once daily and placebo for 6 weeks. Plasma levels of fluticasone propionate were detectable in all 3 active groups, but the mean values were highest in the oral group. Both doses of inhaled fluticasone propionate were effective in maintaining asthma stability and improving lung function, while oral fluticasone propionate and placebo were ineffective. This demonstrates that the clinical effectiveness of inhaled fluticasone propionate is due to its direct local effect and not to an indirect effect through systemic absorption.

CLINICAL TRIALS

Adult and Adolescent Patients 12 Years of Age and Older

Four randomized, double-blind, parallel-group, placebo-controlled, US clinical trials were conducted in 1,036 adolescent and adult patients (≥12 years of age) with asthma to assess the efficacy and safety of fluticasone propionate inhalation powder in the treatment of asthma. Fixed dosages of 100, 250, and 500 mcg twice daily were compared with placebo to provide information about appropriate dosing to cover a range of asthma severity. Patients in these studies included those not adequately controlled with bronchodilators alone and those already maintained on daily inhaled corticosteroids. All doses were delivered by inhalation of the contents of 1 or 2 blisters from the DISKUS twice daily.

Figures 1 through 4 display results of pulmonary function tests (mean percent change from baseline in FEV₁ prior to AM dose) for 3 recommended dosages of fluticasone propionate inhalation powder (100, 250, and 500 mcg twice daily) and placebo from the four 12-week trials in adolescents and adults. These trials used predetermined criteria for lack of efficacy (indicators of worsening asthma), resulting in withdrawal of more patients in the placebo group. Therefore, pulmonary function results at Endpoint (the last evaluable FEV₁ result, including most patients’ lung function data) are also displayed. Pulmonary function at recommended dosages of fluticasone propionate improved significantly compared with placebo by the first week of treatment, and improvement was maintained for up to 1 year or more.

Figure 1. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adolescents and Adults Receiving Bronchodilators Alone

Figure 2. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 100 mcg Twice Daily in Adolescents and Adults Receiving Inhaled Corticosteroids

Figure 3. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 250 mcg Twice Daily in Adolescents and Adults Receiving Inhaled Corticosteroids or Bronchodilators Alone

Figure 4. A 12-Week Clinical Trial Evaluating FLOVENT DISKUS 500 mcg Twice Daily in Adolescents and Adults Receiving Inhaled Corticosteroids or Bronchodilators Alone

In all 4 efficacy trials, measures of pulmonary function (FEV₁) were statistically significantly improved as compared with placebo at all twice-daily doses. Patients on all dosages of FLOVENT DISKUS were also less likely to discontinue study participation due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and patient-recorded variables such as AM PEF, albuterol use, and nighttime awakenings due to asthma) compared with placebo.

In a clinical trial of 111 patients with severe asthma requiring chronic oral prednisone therapy (average baseline daily prednisone dose was 14 mg), fluticasone propionate given by inhalation powder at doses of 500 and 1,000 mcg twice daily was evaluated. Both doses enabled a statistically significantly larger percentage of patients to wean successfully from oral prednisone as compared with placebo (75% of the patients on 500 mcg twice daily and 89% of the patients on 1,000 mcg twice daily as compared with 9% of patients on placebo). Accompanying the reduction in oral corticosteroid use, patients treated with fluticasone propionate had significantly improved lung function and fewer asthma symptoms as compared with the placebo group.

Pediatric Experience

A 12-week, placebo-controlled clinical trial was conducted in 437 patients (177 on fluticasone propionate via DISKUS) aged 4 to 11 years, approximately half of whom were receiving inhaled corticosteroids at baseline. In this study, doses of fluticasone propionate inhalation powder 50 and 100 mcg twice daily significantly improved FEV₁ (15% and 18% change from baseline at Endpoint, respectively) compared to placebo (7% change). Morning peak expiratory flow rate was also significantly improved with doses of fluticasone propionate 50 and 100 mcg twice daily (26% and 27% change from baseline at Endpoint, respectively) compared to placebo (14% change). In this study, patients on active treatment were significantly less likely to discontinue treatment due to asthma deterioration (as defined by predetermined criteria for lack of efficacy including lung function and patient recorded variables such as AM PEFR, albuterol use, and nighttime awakenings due to asthma).

Two other 12-week placebo-controlled clinical trials were conducted in 504 pediatric patients with asthma, approximately half of whom were receiving inhaled corticosteroids at baseline. In these studies, fluticasone propionate inhalation powder was efficacious at doses of 50 and 100 mcg twice daily when compared to placebo on major endpoints including lung function and symptom scores. Pulmonary function improved significantly compared with placebo by the first week of treatment, and patients treated with fluticasone propionate were also less likely to discontinue study participation due to asthma deterioration. One hundred ninety-two (192) patients received fluticasone propionate for up to 1 year during an open-label extension. Data from this open-label extension suggested that lung function improvements could be maintained up to 1 year.