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Alvesco

Alvesco

CLINICAL PHARMACOLOGY

Mechanism of Action

Ciclesonide, is a prodrug, that is enzymatically hydrolyzed to a pharmacologically active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1) following oral inhalation. Des-ciclesonide has anti-inflammatory activity with affinity for glucocorticoid receptors that is 120 times greater than the parent compound and 12 times greater than dexamethasone. The clinical significance of these findings is unknown.

The precise mechanisms of corticosteroid action in asthma are unknown. Inflammation is recognized as an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids may 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 four weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer.

Pharmacodynamics

The effect of ciclesonide by oral inhalation on the HPA axis was assessed in adults with mild asthma in a 29-day placebo controlled study. Twenty-four-hour urinary free cortisol was assessed in a total of 59 adults who were randomized to 320 mcg or 640 mcg ALVESCO, a comparator corticosteroid, or placebo twice daily. At the end of 29 days of treatment, the mean (SE) change from baseline in 24 hr urinary free cortisol was -8.69 (5.6) mcg/day, -4.01 (5.03) mcg/day, and -8.84 (5.02) mcg/day for the placebo, ALVESCO 640 mcg/day, and ALVESCO 1280 mcg/day, respectively. The difference from placebo for the change from baseline in 24 hr urinary cortisol was +4.7 mcg/day [95% CI: -10.58; 19.93] and -0.16 mcg/day [95% CI: -15.20; 14.89] for the 640 mcg/day or 1280 mcg/day treatments, respectively. The effects observed with the comparator corticosteroid validate the sensitivity of the study to assess the effect of ciclesonide on the HPA axis.

Pharmacokinetics

Absorption

Ciclesonide and des-ciclesonide have negligible oral bioavailability (both are less than 1%) due to low gastrointestinal absorption and high first-pass metabolism. Serum concentrations of ciclesonide and des-ciclesonide were measured and compared following oral inhalation of 1280 mcg ALVESCO and intravenous administration of 800 mcg ciclesonide. The absolute bioavailability of ciclesonide was 22% and the relative systemic exposure of des-ciclesonide was 63%. The mean Cmax for des-ciclesonide was 1.02 ng/mL (range 0.6-1.5 ng/mL) in asthmatic patients following a single dose of 1280 mcg by oral inhalation. The mean Cmax (0.369 ng/mL) and AUC0-∞ (2.18 ng*hr/mL) of des-ciclesonide following multiple dose administration of ciclesonide 320 mcg once daily increased up to 26% compared to single dose administration.

Distribution

Following intravenous administration of 800 mcg of ciclesonide, the volumes of distribution of ciclesonide and des-ciclesonide was approximately 2.9 L/kg and 12.1 L/kg, respectively. The percentage of ciclesonide and des-ciclesonide bound to human plasma proteins averaged ≥ 99% each, with ≤ 1% of unbound drug detected in the systemic circulation. Desciclesonide is not significantly bound to human transcortin.

Metabolism

Ciclesonide is hydrolyzed to a biologically active metabolite, des-ciclesonide, by esterases. Des-ciclesonide undergoes further metabolism in the liver to additional metabolites mainly by the cytochrome P450 (CYP) 3A4 isozyme and to a lesser extent by CYP 2D6. The full range of potentially active metabolites of ciclesonide has not been characterized. After intravenous administration of 14C-ciclesonide, 19.3% of the resulting radioactivity in the plasma is accounted for by ciclesonide or des-ciclesonide; the remainder may be a result of other, as yet, unidentified multiple metabolites.

Elimination

Following intravenous administration of 800 mcg of ciclesonide, the clearances of ciclesonide and des-ciclesonide were high (approximately 152 L/L/hr and 228 L/L/hr, respectively). 14C-labeled ciclesonide was predominantly excreted via the feces after intravenous administration (66%) indicating that excretion through bile is the major route of elimination. Approximately 20% or less of des-ciclesonide was excreted in the urine. The mean half life of ciclesonide and des-ciclesonide was 0.71 hours and 6 to 7 hours respectively. Tmax of des- ciclesonide occurs at 1.04 hours following inhalation of ciclesonide.

Special Populations

Population pharmacokinetic analysis showed that characteristics of des-ciclesonide after oral inhalation of ciclesonide were not appreciably influenced by a variety of subject characteristics such as body weight, age, race, and gender.

Renal Insufficiency

Studies in renally-impaired patients were not conducted since renal excretion of desciclesonide is a minor route of elimination ( ≤ 20%).

Hepatic Insufficiency

Compared to healthy subjects, the systemic exposure of des-ciclesonide (Cmax and AUC) in patients with moderate to severe liver impairment increased in the range of 1.4 to 2.7 fold after 1280 mcg ex-actuator ciclesonide by oral inhalation. Dose adjustment in patients with liver impairment is not necessary.

Pediatric

In 2 clinical safety and efficacy studies conducted in patients 4 to 11 years of age with asthma, population pharmacokinetic samples were obtained in 53 patients for pharmacokinetic analysis. In these pediatric patients, treated with daily doses of 40, 80 or 160 mcg of ALVESCO, the median (min, max) Cmax values of des-ciclesonide were 41 pg/mL (not detectable, 146 pg/mL) (n=11), 113 pg/mL (35, 237 pg/mL) (n=13) and 128 pg/mL (12, 357 pg/mL) (n=14), respectively.

Drug-drug Interactions

In a drug interaction study, co-administration of orally inhaled ciclesonide and oral ketoconazole, a potent inhibitor of cytochrome P450 3A4, increased the exposure (AUC) of ciclesonide active metabolite, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged [see DRUG INTERACTIONS].

In another single-dose drug interaction study, co-administration of orally inhaled ciclesonide and oral erythromycin, an inhibitor of cytochrome P450 3A4, had no effect on the pharmacokinetics of either ciclesonide and the active metabolite, des-ciclesonide, or erythromycin.

Based on in vitro studies in human liver microsomes, des-ciclesonide had no significant potential to inhibit or induce the metabolism of other drugs metabolized by CYP450 enzymes. The inhibitory potential of ciclesonide on CYP450 isoenzymes has not been studied. Based on in vitro human hepatocyte studies, ciclesonide and des-ciclesonide had no potential to induce major CYP450 isozymes.

In vitro studies demonstrated that the plasma protein binding of des-ciclesonide was not affected by warfarin or salicylic acid, indicating no potential for protein binding-based drug interactions.

In a population pharmacokinetic analysis including 98 subjects, co-administration of ALVESCO and albuterol had no effect on the pharmacokinetics of des-ciclesonide.

Concomitant administration of ALVESCO (640 mcg) and formoterol (24 mcg) did not change the pharmacokinetics of either des-ciclesonide or formoterol.

Clinical Studies

Asthma

Adults and Adolescents 12 years of Age and Older

The efficacy of ALVESCO was evaluated in six randomized double-blind, placebo-controlled, parallel-group clinical trials in adult and adolescent patients 12 years of age and older with mild persistent to severe persistent asthma. The six trials include two trials in which patients were treated with ALVESCO administered once daily for 12 weeks, two trials in which patients were treated with ALVESCO twice daily for 12 weeks, and two trials in which patients were treated with ALVESCO using once daily and twice daily dosing regimens for 12 or 16 weeks. These trials included a total of 2843 patients (1167 males and 1676 females) of whom 296 were adolescents 12-17 years of age. The primary efficacy endpoint in four of the six trials was the mean change from baseline in pre-dose FEV1 at endpoint (last observation). FEV1 was measured prior to the morning dose of study medication (at the end of the 24-hour dosing interval for once daily administration, and at the end of the 12-hour dosing interval for twice daily administration). In one of the six trials, the primary endpoint was the change from baseline in the average of the pre-dose FEV1 at Weeks 12 and 16, and in another trial, reduction of oral corticosteroid use was the primary efficacy endpoint. Additional efficacy variables were asthma symptoms, use of albuterol for rescue, AM PEF, nighttime awakenings, and withdrawal due to asthma worsening.

The two once daily dosing trials were identically designed and were conducted to evaluate the efficacy of ALVESCO 80, 160, and 320 mcg given once daily in the morning for 12 weeks in patients with mild to moderate asthma maintained on inhaled bronchodilators and/or corticosteroids. The results of these trials, along with other trials that explored twice daily dosing, indicate that once daily dosing is not the optimum dosing regimen for ALVESCO.

Four trials were designed to evaluate the efficacy of ALVESCO administered twice daily in patients with asthma who were previously maintained on bronchodilators alone, patients who were previously maintained on inhaled corticosteroids, and patients who were previously maintained on oral corticosteroids.

Patients Previously Maintained on Bronchodilators Alone

The efficacy of ALVESCO was studied in a randomized, double-blind, placebo-controlled trial in 691 patients with mild-to-moderate persistent asthma (mean baseline percent predicted FEV1 of 72%) previously using reliever therapy (bronchodilator therapy alone). In this trial, patients were treated with ALVESCO 160 mcg once daily in the morning for 16 weeks, ALVESCO 80 mcg twice daily for 16 weeks, or ALVESCO 80 mcg twice daily for 4 weeks followed by ALVESCO 160 mcg once daily in the morning for 12 weeks or placebo for 16 weeks. Compared to placebo, all ALVESCO doses showed statistically significant improvement at week 16 in AM pre-dose FEV1. However, the increase in AM pre-dose FEV1 in the patients treated with ALVESCO 80 mcg twice daily was significantly greater than that observed in patients treated with ALVESCO 160 mcg administered once daily. Compared to placebo, increases in AM pre-dose FEV1 were 0.12 L or 5.0 % for ALVESCO 160 mcg once daily, 0.24 L or 10.4 % for ALVESCO 80 mcg twice daily, 0.13 L or 5.0 % for ALVESCO 80 mcg twice daily for 4 weeks followed by ALVESCO 160 mcg once daily. Other measures of asthma control AM PEF, and need for rescue albuterol also improved in all the ALVESCO treatment groups compared to placebo but the improvement was greatest with the ALVESCO 80 mcg twice daily treatment arm. Discontinuations from the study for lack of efficacy were lower in the ALVESCO treatment groups compared to placebo. Fewer patients receiving ALVESCO experienced asthma worsening than did patients receiving placebo. The AM pre-dose FEV1 results are shown in Figure 1 below.

Figure 1: A 16-Week Double-Blind Clinical Trial Evaluating ALVESCO Administered Once Daily, Twice Daily, or Twice Daily Initially for 4 Weeks Followed by Once Daily for 12 Weeks, in Adult and Adolescent Patients with Mild-to-Moderate Asthma Previously Maintained on Bronchodilators Alone: Mean Change from Baseline in FEV1 (L) prior to AM dose

Mean Change from Baseline in FEV1 (L) prior to AM dose - Illustration

Patients Previously Maintained on Inhaled Corticosteroids

The efficacy of ALVESCO in asthma patients previously maintained on inhaled corticosteroids was evaluated in two randomized double-blind placebo controlled trials of 12weeks treatment duration. In one trial, asthmatic patients with mild to moderate persistent asthma (mean baseline percent predicted FEV1 of 79%), previously maintained on controller therapy (predominantly inhaled corticosteroids) were treated with ALVESCO 160 mcg once daily in the morning, ALVESCO 80 mcg twice daily or placebo.

The AM pre-dose FEV1 results are shown in Figure 2 below.

Figure 2: A 12-Week Double-Blind Clinical Trial Evaluating ALVESCO Administered Once and Twice Daily in Adult and Adolescent Patients with Mild-to-Moderate Asthma Previously Maintained on Inhaled Corticosteroids: Mean Change from Baseline in FEV1 (L) prior to AM dose

The AM pre-dose FEV1 results - Illustration

Statistically significantly more increases in AM pre-dose FEV1 compared to placebo were seen at 12 weeks for ALVESCO 160 mcg once daily (0.14 L or 5.7%) and ALVESCO 80 mcg twice daily (0.19 L or 7.5%). Asthma symptoms scores, AM PEF, and decreased need for rescue albuterol remained relatively stable in the ALVESCO treatment groups compared to slight worsening in the placebo. Compared to placebo, fewer patients receiving ALVESCO experienced worsening of asthma.

In the other trial, 257 patients with moderate to severe persistent asthma (mean baseline percent predicted FEV1 of 54%) were treated with ALVESCO 160 or 320 mcg twice daily for 12 weeks. The AM pre-dose FEV1 results are shown in Figure 3 below.

Figure 3: A 12-Week Double-Blind Clinical Trial Evaluating ALVESCO Administered Twice Daily in Adult and Adolescent Patients with Severe Asthma: Mean Change from Baseline in FEV1 (L) prior to AM dose

Mean Change from Baseline in FEV1 (L) prior to AM dose - Illustration

Compared to placebo, both ALVESCO doses showed statistically significantly more improvement in pre-dose FEV1 (0.11 L or 8.6% and 0.18 L or 11.8%). Other measures of asthma control, AM PEF, symptoms, and need for rescue albuterol also showed improvement compared to placebo. Compared to placebo, fewer patients treated with ALVESCO experienced worsening of asthma.

Patients treated with ALVESCO were also less likely to discontinue study participation due to asthma deterioration.

Patients Previously Maintained on Oral Corticosteroids

In a 12-week double-blind clinical trial, 140 patients with severe persistent asthma (mean FEV1 at baseline 53% predicted) who had failed prior efforts to eliminate oral prednisone use and had established their lowest effective prednisone dose were randomized to ALVESCO given by inhalation aerosol at doses of 320 or 640 mcg twice daily or placebo. The average prednisone dose at baseline was approximately 12 mg/day. Compared to patients on placebo whose prednisone requirements increased by 4%, those treated with ALVESCO 320 mcg and 640 mcg twice daily significantly reduced their prednisone requirements by 47% and 62% respectively. At the same time, patients on ALVESCO maintained asthma control as reflected by lung function, symptoms, and need for rescue albuterol. A significantly larger percentage of patients on ALVESCO were able to reduce oral prednisone use by 50% or more as compared to placebo (64% and 77% of the patients treated with 320 mcg and 640 mcg respectively twice daily as compared with 33% of patients on placebo). There was no statistically significant difference observed with ALVESCO 640 mcg twice daily compared to ALVESCO 320 mcg twice daily.

Pediatric Patients less than 12 Years of Age

Two identically designed randomized, double-blind, parallel, placebo-controlled clinical trials of 12 weeks treatment duration were conducted in 1018 patients aged 4 to 11 years with asthma but efficacy was not established. In addition, one randomized, double-blind, parallel, placebo-controlled clinical trial did not establish efficacy in 992 patients aged 2 to 6 years with asthma. Clinical trials have not been conducted in pediatric patients less than 2 years of age. [see Pediatric Use]

Last reviewed on RxList: 1/14/2013
This monograph has been modified to include the generic and brand name in many instances.

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